Circulation. 1997;96:2069-2077
(Circulation. 1997;96:2069-2077.)
© 1997 American Heart Association, Inc.
Cardiac Allograft Vasculopathy
A Review
Michael Weis, MD;
;
Wolfgang von Scheidt, MD
From Medizinische Klinik und Poliklinik I, Klinikum Grosshadern,
University of Munich, Germany.
Correspondence to Dr Michael Weis, Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, University of Munich, Marchioninistraße 15, 81377 Munich, Germany. E-mail Micha.Weis{at}t-online.de
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Abstract
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Abstract Cardiac allograft vasculopathy (CAV) remains a
troublesome
long-term complication of heart transplantation. It is
manifested
by a unique and unusually accelerated form of
coronary disease
affecting both intramural and epicardial
coronary arteries and
veins. CAV is characterized by vascular
injury induced by a
variety of noxious stimuli, including the immune
system response
to the allograft, ischemia-reperfusion injury,
viral infection,
immunosuppressive drugs, and classic risk factors such
as hyperlipidemia,
insulin resistance, and
hypertension. The obstructive vascular
lesions are thought to progress
through repetitive endothelial
injury followed by
repair response. The role of major histocompatibility
complex
donor-recipient differences in the pathogenesis of CAV
has not yet been
completely elucidated. Intracoronary ultrasound
studies reveal
a dual morphology with donor-transmitted or de
novo focal,
noncircumferential plaques in proximal segments
and/or a diffuse,
concentric pattern observed in distal segments.
A lack of correlation
between microvascular and epicardial vessel
disease suggests discordant
manifestations and progression of
CAV. Apoptosis and loss of
functional vascular remodeling have
to be considered as important
mediators of clinically relevant
CAV. Strategies for blocking T-cell
costimulation and expression
of adhesion molecules may help prevent
chronic rejection in
clinical transplantation.
3-Hydroxy-3-methylglutaryl coenzyme
A reductase inhibitors
and antiproliferative drugs may slow
progression of CAV by various
effects. Methods to augment endogenous
nitric oxide
bioavailability as well as newer immunosuppressive
regimens may be
protective. Balloon angioplasty has a limited
role in the treatment of
focal lesions. Experiences with coronary
stenting,
coronary artery bypass grafting, and transmyocardial
laser
revascularization are limited. Retransplantation
has a
worse outcome than initial transplantation.
Key Words: transplantation vasculopathy coronary disease endothelium
 |
Introduction
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Cardiac
allograft vasculopathy remains a troublesome long-term
complication of
heart transplantation and is the major cause
of death in patients
surviving 1 year after transplantation.
1 It is manifested
by a unique and unusually accelerated form
of coronary disease
affecting both intramyocardial and epicardial
coronary arteries
and veins.
2 Although the disease selectively
involves the
vascular bed of the allograft, including the donor
aortic segment, all
other native vessels throughout the body
are spared. Rapid or fulminant
development of CAV within 1 year
portends a poor prognosis for major
clinical events.
3 Although
there is evidence of partial
reinnervation of the cardiac allografts,
most heart transplant
recipients cannot experience typical anginal
pain associated with
myocardial ischemia or infarction. The
first clinical
manifestations, therefore, are often ventricular
arrhythmias,
congestive heart failure, or sudden death. At 1,
2, and 4 years,
the actuarial likelihood of any angiographically
visible CAV
is 11%, 22%, and 45%, respectively, as demonstrated in a
multi-institutional
study.
4 Intimal thickening is
detectable with ICUS in up to
75% of patients at year 1.
5
With the development of animal
models of CAV, the use of ICUS, and
pharmacological testing
of coronary vasomotor function, new
insights into the pathogenesis,
functional and morphological patterns,
and progression of CAV
are possible. This article evaluates the
pathological characteristics,
immunopathology, pathophysiology,
diagnosis, and treatment options,
as well as future directions of CAV
research.
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Pathological Characteristics
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The histological changes that characterize CAV are
not uniform.
Pathological examination of coronary arteries from
human cardiac
allografts has shown a broad spectrum of abnormalities,
ranging
from concentric fibrous intimal thickening to complicated
atherosclerotic
plaques that bear a close resemblance to spontaneous
atherosclerosis.
6 It has been demonstrated
that early intimal proliferation progresses
with time and with
subsequent increases in lipid deposits and
calcification of the
coronary vessel.
2 Atheromas and
diffuse
intracellular and extracellular accumulation of lipids in both
intimal
and medial walls are frequent occurrences.
7 The
internal elastic
lamina remains almost intact except for small
breaks.
2 A time-dependent
spectrum of histopathological
changes has been described.
8 Early after transplantation,
diffuse fibrous intimal thickening
or a vasculitis predominates. Late
after transplantation, focal
atherosclerotic plaques, diffuse intimal
thickening, or a mixture
of both is found. The smaller branches are
often occluded before
the larger epicardial arteries, resulting in
small, stellate
infarcts.
9 Despite exuberant intimal
proliferation, the media
of the vessel is rarely thickened and
sometimes becomes narrower
than in normal conditions.
10
The cellular infiltrate of intimal
proliferative lesions consists of
modified smooth muscle cells,
macrophages/monocytes, and T
lymphocytes.
10
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Pathophysiology/Immunopathology
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Although the exact pathogenesis of CAV remains to be established,
several
lines of data suggest that it is primarily an immune-mediated
disease.
Limitation of the proliferative vascular disease to the
allograft
arterial and venous tree, the often diffuse
nature of allograft
vascular involvement, the development of CAV in
cardiac allografts
of animal models with some histocompatibility
mismatch, and
the lack of development in isografts support the
immunologic
hypothesis of CAV development. Several experimental models
suggest
that immunologic mechanisms operating in a milieu of
nonimmunologic
risk factors constitute the principal stimuli that
result in
progressive myointimal hyperplasia. The initial event of CAV
is
probably a subclinical graft coronary
endothelial injury. The
endothelial
cell is the major determinant of vessel wall function.
It normally
inhibits thrombus formation and leukocyte adhesion,
regulates vasomotor
function, and inhibits vascular smooth muscle
cell proliferation.
Damage to the endothelium could alter any
or all of
these functions, predisposing the artery to inflammation,
thrombosis,
vasoconstriction, and vascular smooth muscle cell
growth.
11 After human cardiac transplantation, humoral or
more important
cellular responses to HLA antigens and vascular
endothelial
cell antigens are potential sources of
endothelial damage. CD4
lymphocyteinduced
upregulation of MHC class II antigens
on endothelial
cells (subsequent to MHC-I antigen detection
by CD8 lymphocytes)
elicits a cellular immune response.
12 The
role of MHC
donor-recipient differences in the pathogenesis
of CAV has not yet been
completely elucidated. However, HLA
class I or class II mismatching was
not found to be associated
with posttransplant coronary
atherosclerosis in a large, single-center
study.
13 The ability to produce CAV in animals
transplanted with an
MHC-identical graft and, more recently, to
document the occurrence
of allograft rejection in genetically
engineered animals lacking
MHC genes should spur further investigations
of other allograft-specific
antigens, distinct from those of the MHC,
which may play an
important role in the development of
CAV.
14 Irrespective of
the initial specific
immune-mediated injury, the cascade of
events that follows appears to
be a physiologically nonspecific
inflammatory
response.
15 It is important to note that activated
lymphocytes
secrete interferon-

, which stimulates production
of ICAM-1.
16 The involvement of adhesion molecules plays a
crucial role
in regulating the interaction of inflammatory cells with
cells
in the vascular wall because the adherence of leukocytes to
vascular
endothelium is a prerequisite for
transmigration. Expression
of vascular adhesion molecules (VCAM-1,
ICAM-1, and ELAM-1)
on endothelial cells and medial
smooth muscle cells in cardiac
transplant patients has been
observed,
17 and early ICAM-1 expression
could be
correlated to early development of angiographically
visible
CAV.
18 The intercellular network, via macrophages,
T
lymphocytes, endothelial cells, and smooth muscle
cells, generates
a variety of stimulatory cytokines (IL-1,
IL-2, IL-6, and tumor
necrosis factor-

) and growth factors (PDGF,
IGF-I, FGF, HBGF,
EGF, GM-CSF, and TGF-ß) that promote the
development of
the chronic allograft lesion.
15 Thus, at
the end of the "endothelial
injury process,"
chronic inflammation elicits a repair response
that causes the
production of a connective tissue matrix
19 and the
migration and proliferation of vascular wall smooth
muscle cells that
compromise the vascular lumen. Recently apoptosis,
a
genetically encoded cell-death program, has been proposed
to be
involved in human coronary atherosclerosis,
especially
during restenosis.
20 Dong et
al
21 demonstrated a pathological
evidence for Fas-mediated
apoptotic cytotoxicity in CAV. Nitric
oxide has the capacity to
influence apoptosis
22 and is induced
during
cardiac allograft rejection.
23 Moreover, induction of
inducible
nitric oxide synthase was associated with CAV in a rat
cardiac
allograft transplant model.
24 Conceivably, there
is a possible
link between nitric oxidemediated apoptosis in
smooth
muscle cells and transplant intimal thickening.
However, the development of clinically evident CAV depends on the
interplay between the lesion-formation response of the allograft to
injury versus the adaptive process of vascular
remodeling.25 The expansion of the intimal lesion
eventually overcomes the capacity of the vessel to undergo compensatory
enlargement remodeling such that the plaque creates a vessel
stenosis. Indeed, the pathogenesis of clinically relevant CAV
may be due in part to the possible lack of compensatory dilation
(enlargement) of the vessel wall over time.26
Intriguingly, dilated angiopathy, a specific subtype of
CAV,27 might be an example of overcompensating positive
remodeling.
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Alloantigen Independent Risk Factors
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Several nonimmunologic mechanisms could contribute to the
progression
of CAV. These include recipient characteristics (age, sex,
obesity,
hypertension, hyperlipidemia, insulin
resistance, and CMV infection)
and donor characteristics (age, sex,
preexisting coronary disease,
and donor ischemic
time).
28 29 30 Preliminary insights from
a multicenter ICUS
study
31 indicated that there is no apparent
association
between the progression of intimal thickening and
multiple nonimmune
factors, including donor and recipient characteristics
(recipient or
donor age and sex, sex mismatch, pretransplant
diagnosis,
ischemic time, posttransplant hypertension, body
mass index,
and CMV infection).
Metabolic Risk Factors
Glucose intolerance and insulin resistance,
hypercholesterolemia,
hypertriglyceridemia, and low HDL cell
surface levels occur in 50% to 80% of patients after cardiac
transplantation.32 In vitro studies33 have
shown that LDL cholesterol, particularly its oxidized
derivatives, is injurious to the endothelium.
Hypercholesterolemia can impair
endothelium-dependent vasorelaxation via oxidative
inactivation of nitric oxide, and the damaged
endothelium is a source of excess superoxide anion. A
close relation between abnormalities in lipids and coronary
artery endothelial dysfunction has been demonstrated in
patients with atherosclerosis, but not after human
heart transplantation.34 35 However, in a multicenter ICUS
study,36 an insignificant trend with
triglyceride level and an inverse relationship between HDL
cholesterol level and intimal thickening was observed.
Intimal thickening was more pronounced in those patients with higher
LDL/HDL cholesterol ratios. The
high-triglyceride/low-HDL cholesterol levels
associated with atherosclerosis are well described,
particularly in patients who demonstrate the syndrome of insulin
resistance.37 Indeed, Valantine et al38
demonstrated that glucose intolerance and insulin resistance,
frequently observed after heart transplantation, were strong predictors
of intravascularly visible CAV.
CMV
Human CMV has been associated with CAV.39 The
endothelium is a common target for CMV infection, and
the immediate early gene of human CMV can code for a protein that has
sequence homology and immunologic cross-reactivity with a domain of
HLA-DR.40 Preliminary data from Briggs et
al41 provide information regarding virally induced
molecular events that may serve to promote host mononuclear adhesion,
activation, and transendothelial migration within the
allograft vasculature. Additionally, the CMV-induced blockage of the
regulatory role of p53,42 a protein that inhibits
proliferation of smooth muscle cells and apoptosis, might
accelerate the progression of CAV.43 Cytokines
associated with CMV infection, as well as virus-related factors such as
dysregulation of cellular lipid metabolism, may also
increase endothelial damage and vasculopathic changes.
However, Gulizia et al44 recently observed that the
presence of the human CMV genome is not associated with the nature or
extent of CAV. Thus, additional pathological and molecular work is
needed to determine whether or how CMV infection may be involved
pathogenically in CAV.
Ischemia-Reperfusion Injury
The role of ischemia and reperfusion has to be considered
as an early, transient (but important) cofactor of
endothelial injury45 46 after
transplantation. Presumably, beginning from an activation of the
microvascular endothelium, free oxygen radicals lead to
a subsequent activation of passing host leukocytes and
macrophages. Activated cells release oxygen radicals
and other aggressive mediators, such as proteases, cytokines,
and eicosanoids, which chemotactically attract host leukocytes. Thus,
postischemic reperfusion injury in total represents
the result of network interactions mediated by a large variety of
oxidative molecules and aggressive mediators. The primary
endothelial injury is transferred to
interstitial injury.47
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Diagnosis
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Noninvasive Screening
Noninvasive screening tests such as exercise
electrocardiography,
thallium
scintigraphy, exercise radionuclide ventriculography,
and
ambulatory electrocardiography are generally
not sensitive
or specific enough to be considered reliable screening
tests.
48 Conflicting data have been reported concerning
the accuracy
of stress echocardiography in
diagnosing CAV.
49 50
Coronary Angiography
Although coronary angiography may be specific in the
diagnosis of CAV, it has been shown to underestimate the presence of
disease and therefore has not proven to be a sensitive method of
diagnosis. The insensitivity of coronary angiography in the
diagnosis of CAV, except for significant focal stenoses, has
been demonstrated by histopathologic studies51 and by
comparison with ICUS.52 This may result from the fact that
severe intimal thickening may be compensated by vessel-enlarging
remodeling. Additionally, in the rare case of homogeneous
intimal proliferation, a reference vessel segment, required to detect
luminal narrowing, may be missing. Although no correlation between the
severity of CAV and left ventricular ejection fraction is
detectable,53 the development of significant epicardial
coronary stenoses does convey a poor prognosis with a
high degree of specificity.54 It is likely that
angiographic luminal irregularities indicate a change not only in the
volume but also in the character of the plaque mass.
ICUS
More recently, ICUS has been investigated as an imaging modality
in the coronary arteries of heart transplant recipients. This
technique allows a reproducible look at both actual lumen diameter and
the appearance and thickness of the intima and media. An intravascular
ultrasound study in 132 patients 1 to 9 years after transplantation
detected atherosclerosis in >80% of patients, with
proximal segments most frequently (focally) involved.55
Diffuse and circumferential atherosclerosis was more
common in mid and distal segments. Tuzcu et al56 described
unequivocal atherosclerosis in 56% of recipients
studied within 1 month after transplantation, representing
donor-transmitted disease. These intravascular studies suggest that CAV
has a dual origin, with many donor-transmitted early, focal,
noncircumferential plaques in proximal segments. The diffuse,
concentric pattern observed in distal segments likely
represents the result of an overlapping immune-mediated vessel
injury. Botas et al57 noted that preexistent donor
coronary disease does not accelerate the progression of CAV
within the first few years after transplantation. Importantly, the
first prospectively collected, multicenter, intravascular study
database of 299 heart transplant recipients5 indicated
that the most rapid rate of progression of intimal thickening occurs
during the first year after the transplant procedure (intimal thickness
at baseline was 190±18 µm, and this thickness increased to
300±26 µm), followed by slow but inexorable progression over
time. The presence of moderate to severe intimal thickening by ICUS is
predictive of the future development of angiographically apparent
CAV.58 Moreover, in a recent study that assessed the
clinical predictive value of ICUS, Mehra et al59
demonstrated that cardiac transplant recipients with severe intimal
thickening were 10-fold more likely to suffer cardiac events than those
without severe hyperplasia. Because many heart transplant recipients
with severe intimal thickening remain free of clinical morbid events,
additional studies must consider the importance of the quality and not
merely the quantity of intimal proliferation, as well as compensatory
remodeling, in determining prediction of morbid cardiac events. The
question of whether ICUS is superior to angiography with respect to
direct therapeutic consequences (except for studies evaluating
antiproliferative strategies) remains unanswered. Standardization of
the quantification of intimal thickening by ICUS and the definition of
pathological intimal thickness are continuing problems that must be
solved.
Epicardial Endothelial Function
The consequence of epicardial endothelial
dysfunction, frequently observed in cardiac transplant
patients,60 61 is still unclear. The existence of
coronary segments with functioning endothelium
indicates that the latter is not diffusely disturbed in all cardiac
transplant recipients and that possibly the endothelial
function is not irreversibly lost.62 It is recognized that
the anticoagulant factors synthesized by a well-functioning
endothelium play an important role in determining the
local homeostatic equilibrium and that deficient
fibrinolysis plays a role in the development of
CAV.63 Nitric oxide as an antimitogenic,
antiproliferative substance with antioxidative effects is clearly
involved in the accelerated process of intimal
thickening.64 Recently, Davis et al65
demonstrated that early endothelial dysfunction (15±3
days after transplantation) predicts the development of intravascular
ultrasoundvisible CAV at 1 year after heart transplantation.
Preliminary data from Yeung et al66 suggest that early
evidence of endothelial dysfunction may predict an
adverse clinical outcome.
Intracoronary Doppler Flow Velocity
Measurement
Coronary blood flow measurement is an established
functional parameter to assess the integrity of the
microcirculation. Usually, intracoronary Doppler flow is
used to assess the resistance bed of the coronary
microcirculation. Microvascular disease leads to a diminishment in
coronary flow reserve (ratio of hyperemic to resting
blood flow velocities). Coronary flow reserve after cardiac
transplantation was found to be preserved in the first 2 years after
cardiac transplantation,67 68 but conflicting results have
been reported concerning the long-term follow-up even in the absence of
flow-limiting epicardial stenoses.35 67 68 69 A
reduced coronary flow reserve during follow-up might be
attributed to structural changes of the myocardium as a
consequence of subclinical rejection episodes and the development of
left ventricular hypertrophy, or it may
represent a manifestation of CAV that affects microvascular
vessels. To date, the prevalence, nature (endothelium
dependent and/or independent), and consequences of coronary
microvascular dysfunction are not well defined. In a recent study from
Weis et al,70 microvascular vessel disease (detected as
reduced endothelium-independent coronary flow
reserve) was associated with a subsequent reduction in left
ventricular ejection fraction during a 2-year follow-up.
Thus, the impaired coronary flow reserve may lead to chronic,
repetitive left ventricular subendocardial ischemia
and resultant impairment of left ventricular
function.71
Importantly, Clausell et al72 demonstrated that there is
no correlation between microvascular and epicardial vessel disease,
suggesting discordant distribution patterns of CAV. We73
investigated epicardial and microvascular vasodilator function in 110
cardiac transplant recipients (1 to 160 months after transplantation)
and could not find any correlation between epicardial and microvascular
endothelial function nor any correlation between
vasomotor function and epicardial intimal hyperplasia. Differences in
pathobiology and rate of progression of disease, as well as antigen
heterogeneity, in the large and small arteries may
account for the heterogeneous presentation.
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Prophylaxis and Therapy
|
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A preliminary study by Schroeder et al
74 randomly
(not blinded
or placebo controlled) assigned 116 consecutive patients
to
receive either diltiazem or no calcium entry blocker and assessed
this
cohort by baseline and annual angiograms at 1 and 2 years
thereafter.
The patients treated with diltiazem were less likely to
demonstrate
a significant change in their follow-up angiogram and had a
significantly
better survival rate. Calcium antagonists
facilitate the effects
of endothelium-derived relaxing
factors in vascular smooth muscle,
and they also inhibit the
vasoconstrictive effects of endothelin
and
cyclooxygenase contracting factors and thus may
have protective
cardiovascular
properties.
75 However, diltiazem failed to suppress
intimal
proliferation in a rat allograft coronary disease
model.
76 A case-control study by Mehra et
al
77 in 32 consecutive posttransplant
patients
demonstrated that patients treated either with calcium
entry blockers
or with ACE inhibitors have a lesser degree of
intimal
proliferation in the first year after transplantation.
A salutary
effect of ACE inhibitors on CAV was confirmed in
a
Lewis-toFisher 344 rat heterotopic transplant model.
78
Kobayashi et al
78 demonstrated that animals in the
captopril
group showed minimal intimal proliferation and reduced smooth
muscle
cell proliferation for up to 3 months of follow-up. Importantly,
ACE
inhibitors not only prevent the formation of
angiotensin II,
a potent vasoconstrictor with proliferative
properties, but
also augment the local vascular concentrations of
bradykinin
and in turn the activation of the
L-argininenitric oxide
pathway.
79 ACE
inhibitors have been shown to retard the vascular
remodeling
process within the renal microcirculation that promotes
diabetic
nephropathy and eventual kidney
failure.
80 Thus, one may speculate
that vasodilators are
effective in part because of flow-induced
remodeling. Recently, von der
Leyen et al
81 demonstrated the
impact of in vivo gene
transfer of the nitric oxide synthase
gene, which effectively inhibited
intimal lesion formation in
a rat carotid balloon-injury model. The
local delivery of nitric
oxide donors, especially as stable
nitrosothiol compounds, may
have therapeutic benefit in inhibiting the
proliferation of
smooth muscle cells. Even supplementation of
L-arginine, the
precursor of nitric oxide, could
represent a novel therapeutic
strategy to maintain normal
endothelial function after cardiac
transplantation.
82 In a rabbit cardiac allograft model,
L-arginine feeding reduced
coronary artery
myointimal hyperplasia by attenuating the mitogenic
response
of vascular cells to IGF-I and IL-6.
83 Thus,
strategies to
augment endogenous nitric oxidegenerating
capacity and/or
to inhibit the deleterious effects of free oxygen
radicals on
nitric oxide efficacy (bioavailability) may prove to be
protective
against endothelial dysfunction and
development of CAV. Inhibitors
of HMG-CoA reductase have
been associated with a reduced incidence
of severe rejection episodes
and reduced progression of CAV.
29 84 HMG-CoA reductase
inhibitors may slow the progression of
CAV by
immunomodulatory effects independent of cholesterol
reduction.
84 85 86 87 88 Moreover, simvastatin inhibits
growth factorinduced
cell proliferation and modulates platelet
thromboxane-A
2 biosynthesis.
89
Angiopeptin, an octapeptide analogue of somatostatin, was found
to have
immunosuppressive properties, most probably due to inhibition
of IGF-I
and reduction of MHC class II, T lymphocyte, macrophage,
and
ICAM-1 expression.
90 In a rabbit heterotopic heart
transplant
model, angiopeptin has been shown to attenuate myointimal
hyperplasia.
91 Preliminary results from a prospective,
randomized, double-blind,
placebo-controlled clinical trial indicated
that treatment with
angiopeptin for 14 days after heart transplantation
and as an
adjunct treatment during rejection episodes significantly
reduced
intimal proliferation within a follow-up time of 32
months.
92 Because of the early and sustained presence of T
cells and
macrophages in vascular lesions, Russell et
al
93 have used
CTLA4Ig, a fusion protein that blocks the
CD28-B7 costimulatory
T-cell activation pathway, in a rat heterotopic
cardiac transplantation
model. Grafts from long-term (>120 days)
survivors treated
with the fusion protein showed significant reductions
in the
frequency and severity of arteriosclerosis
compared with cyclosporine
Atreated rats. Thus,
strategies for blocking T-cell costimulation
may help prevent chronic
rejection in clinical transplantation.
Clinical and Experimental Immunosuppressive Drugs
Using a predictive model for adverse cardiac events from CAV in a
cohort of 163 consecutive heart transplant recipients, Mehra et
al94 detected a prognostic impact of immunosuppression and
cellular rejection on CAV. Whereas a higher daily
cyclosporine dose was found to be protective for adverse
cardiac events, greater prednisone consumption was substantially
deleterious. Tacrolimus (FK 506), a new macrolide immunosuppressant
agent, appears to exert its effects through a molecular mechanism of
action similar to that of cyclosporine but has been thought
to be more potent, presumably by inhibiting cytokine synthesis
by T cells infiltrating the allograft.95 Meiser et
al96 compared FK 506 to cyclosporine in a rat
cardiac allograft vascular model. Allografted hearts from rats treated
with FK 506 showed a worse grade of CAV than did grafted hearts from
rats treated with cyclosporine. These results could be
confirmed by Arai et al.97 In contrast, Wu et
al98 have described the inhibition of rat heart allograft
arteriosclerosis by FK 506 in recipients of
syngeneic grafts. The intermediate-term results from a prospective
trial99 of FK 506 in clinical heart transplantation
demonstrated no significant difference in actuarial freedom from
angiographically visible CAV at 4 years between patients treated with
FK 506 (n=80) and cyclosporine (n=80). Mycophenolate
mofetil, an antimetabolite derived from mycophenolic acid, was shown to
prolong cardiac allograft survival, induce donor-specific tolerance,
and reverse ongoing acute cellular rejection in rodent and primate
models.95 Gregory et al100 demonstrated a
regression in arterial thickening and
endothelial replacement by mycophenolate mofetil using
a balloon-catheterinduced arterial-injury model in rats.
Thus, the direct antiproliferative action on smooth muscle cells by
mycophenolate mofetil in vivo may retard the development of CAV.
However, mycophenolate mofetil increased tumor necrosis
factor-
induced expression of vascular cell adhesion molecules on
cultured human venous endothelial cells101
and thus may have deleterious effects. 15-Deoxyspergualin, an agent
that directly suppresses macrophage function, including the
expression of HLA-DR antigens, appeared to be superior to
cyclosporine for preventing the development of CAV in a rat
heterotopic heart transplantation model.102 In a rat
aortic allograft model of chronic graft rejection, 15-deoxyspergualin
was shown to partially inhibit all parameters of graft
vascular disease, apparently through immune-mediated
mechanisms.103 Rapamycin and leflunomide interfere with
signals transduced by cytokines and growth factors and thus
interrupt the proliferation of a variety of cells, including B cells,
fibroblasts, and smooth muscle cells.104 105 It is
noteworthy that both these agents are able to reverse
arterial thickening in a rat model of transplant
vasculopathy (Lewis to Fisher 344). Leflunomide was associated with
significant downregulation of circulating anti-donor
antibodies.105 Recently, Gregory et al100
demonstrated that rapamycin can also inhibit vascular lesion formation
after balloon injury, presumably by blocking cell-cycle
progression.106 These studies suggest that the coordinated
blockade of cellular processes common to the immune response and
vascular lesion formation may have particular clinical efficacy in
preventing CAV.
Revascularization Procedures
Coronary artery revascularization in
heart transplant recipients, by use of PTCA,107 108
directional coronary atherectomy,109 or
coronary artery bypass graft surgery,110 has been
performed in selected patients as palliative therapy to decrease
ischemia-related morbidity and mortality. Although helpful in
the short-term setting, the long-term results are disappointing, most
probably because of the rapid and diffuse nature of the disease.
Recently, 13 medical centers retrospectively analyzed their
complete experience with different
revascularization procedures.111
Sixty-six patients underwent coronary angioplasty. Angiographic
success (<50% residual stenoses) occurred in 153 of 162
lesions. Forty patients (61%) were alive without retransplantation at
19±14 months after angioplasty. Two patients sustained periprocedural
myocardial infarction and died. Angiographic restenosis
occurred in 42 (55%) of 76 lesions at 8±5 months after angioplasty.
Angiographic distal arteriopathy adversely affected allograft survival.
Thus, balloon angioplasty has comparable primary success rates but is
characterized by a high restenosis rate and progression of CAV
in non-PTCA segments, thus limiting the long-term benefit. There is a
growing number of patients who have symptomatic, diffuse
CAV that is not amenable to mechanical intervention and maximal medical
therapy. Preliminary data suggest evidence of clinical efficacy in
relieving anginal symptoms and improving myocardial perfusion by
transmyocardial laser revascularization in 12 heart
transplant recipients,112 but long-term results are
needed.
Retransplantation
Repeat cardiac transplantation has been performed, but survival
after retransplantation is shorter than after the initial
transplantation.113 114 115 This increased mortality occurs
predominantly during the early posttransplant period and is due in part
to a more frequent requirement for preoperative mechanical assistance,
a higher level of HLA sensitization, and more frequent surgical
complications.114 A shorter interval between transplants
and rejection as the cause of allograft failure are predictors of
increased mortality. Infection, rejection, and development of CAV
probably do not occur more frequently after repeat transplantation,
whereas the incidence of malignancy is double that observed in primary
transplant recipients.114 In view of the limited donor
supply, a number of centers no longer recommend retransplantation. The
individual clinician must balance the therapeutic obligation to the
transplant recipient with the current limitations in the supply of
organs.
 |
Summary and Conclusion
|
|---|
CAV is characterized by vascular injury induced by a variety
of
noxious stimuli, including the immune system response to
the allograft,
ischemia-reperfusion injury, viral infection,
immunosuppressive
drugs, and classic risk factors. The obstructive
vascular lesion
characteristics of CAV are thought to progress
through repetitive
endothelial injury followed by repair response.
T
lymphocytes, macrophages, and neutrophils migrate to the
subendothelial
area via the activity of
endothelial adhesion molecules and,
in turn, elaborate
various cytokines and growth factors that
cause progression of
the process. The role of donor-recipient
MHC differences in the
pathogenesis of CAV has not yet been
completely elucidated, and
experimental models within species
(such as pigs) that, like humans,
express MHC class II on the
endothelium could be
useful.
ICUS studies demonstrate a resemblance to conventional
atherosclerosis as evidenced by eccentric rather than
concentric lesions, branch vessel location, and a large intravessel and
intervessel variability in type and extent of disease in a given
patient. The diffuse, concentric pattern observed in distal segments
likely represents the result of the process of the response to
endothelial injury. Because many heart transplant
recipients with severe intimal thickening remain free of clinical
morbid events, additional studies should consider the importance of the
quality and not merely the quantity of intimal proliferation in
determining the occurrence of morbid cardiac events. Additionally, the
lack of a correlation between microvascular and epicardial vessel
disease suggests different subtypes of CAV. Differences in pathobiology
and the rate of progression of disease in the large and small arteries
may account for the heterogeneous presentation.
Apoptosis and loss of functional vascular remodeling must be
considered as important mediators of clinically relevant CAV in the
future. Strategies for blocking T-cell costimulation and expression of
adhesion molecules may help to prevent long-term rejection in clinical
transplantation. HMG-CoA reductase inhibitors and
antiproliferative drugs may slow the progression of CAV by different
immunologic and nonimmunologic effects. Methods to augment
endogenous nitric oxide metabolism capacity (by
use of ACE inhibitors, L-arginine, or
antioxidants) may be protective against endothelial
injury. The central role of immunosuppressive drugs in the natural
history of CAV is obvious. Newer immunosuppressive drugs may emerge
that will be shown to be protective of (or even deleterious for) the
development of CAV, making randomized clinical trials using ICUS
necessary. Revascularization procedures have an
established but very limited role in the setting of significant focal
lesions. Retransplantation is associated with an increased mortality
and is discussed controversially in the face of organ shortage. With a
better understanding of the causes of CAV and the development of
specific treatment options to halt or prevent this form of vascular
disease, the lifetime of allografts may be extended in most
recipients.
 |
Selected Abbreviations and Acronyms
|
|---|
| CAV |
= |
cardiac allograft vasculopathy |
| CMV |
= |
cytomegalovirus |
| HMG-CoA |
= |
3-hydroxy-3-methylglutaryl coenzyme A |
| ICAM-1 |
= |
intercellular adhesion molecule-1 |
| ICUS |
= |
intracoronary ultrasound |
| IGF |
= |
insulin-like growth factor |
| IL |
= |
interleukin |
| MHC |
= |
major histocompatibility complex |
| PTCA |
= |
percutaneous transluminal coronary
angioplasty |
|
 |
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