(Circulation. 1997;96:2069-2077.)
© 1997 American Heart Association, Inc.
Articles |
Cardiac Allograft Vasculopathy
A Review
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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 Top Abstract IntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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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
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Introduction |
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TopAbstractIntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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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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TopAbstractIntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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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 lymphocyte–induced 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 matrix19 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
al21 demonstrated a pathological evidence for Fas-mediated
apoptotic cytotoxicity in CAV. Nitric oxide has the capacity to
influence apoptosis22 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 oxide–mediated 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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TopAbstractIntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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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 study31 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
ultrasound–visible 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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TopAbstractIntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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A preliminary study by Schroeder et al74 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 al77 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-to–Fisher 344 rat heterotopic transplant model.78 Kobayashi et al78 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-arginine–nitric 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 al81 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 oxide–generating 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 factor–induced cell proliferation and modulates platelet thromboxane-A2 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 al93 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 A–treated 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-catheter–induced 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.
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Summary and Conclusion |
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TopAbstractIntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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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.
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References |
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TopAbstractIntroductionPathological CharacteristicsPathophysiology/ImmunopathologyAlloantigen Independent Risk...DiagnosisProphylaxis and TherapySummary and ConclusionReferences |
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1. Kaye MP. The Registry of the International Society for Heart and Lung Transplantation: Tenth Official Report—1993. J Heart Lung Transplant. 1993;12:541-548.[Medline] [Order article via Infotrieve]
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N. Kajihara, S. Morita, Y. Tanoue, N. Boku, M. Eto, T. Nishida, and R. Tominaga The UW solution has greater potential for longer preservation periods than the Celsior solution: comparative study for ventricular and coronary endothelial function after 24-h heart preservation. Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 784 - 789. [Abstract] [Full Text] [PDF]
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T. Hattori, H. Shimokawa, M. Higashi, J. Hiroki, Y. Mukai, K. Kaibuchi, and A. Takeshita Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice Circ. Res., January 9, 2004; 94(1): 46 - 52. [Abstract] [Full Text] [PDF]
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A. Hognestad, K. Endresen, R. Wergeland, O. Stokke, O. Geiran, T. Holm, S. Simonsen, J. K. Kjekshus, and A. K. Andreassen Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients J. Am. Coll. Cardiol., August 6, 2003; 42(3): 477 - 482. [Abstract] [Full Text] [PDF]
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G. Vassalli, A. Gallino, M. Weis, W. von Scheidt, L. Kappenberger, L.K. von Segesser, J.-J. Goy, and on behalf of the Working Group Microcirculation of Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy Eur. Heart J., July 1, 2003; 24(13): 1180 - 1188. [Abstract] [Full Text] [PDF]
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M. Weis and J. P. Cooke Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 567 - 575. [Abstract] [Full Text] [PDF]
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J. J. Yun, M. P. Fischbein, D. Whiting, Y. Irie, M. C. Fishbein, M. D. Burdick, J. Belperio, R. M. Strieter, H. Laks, J. A. Berliner, et al. The Role of MIG/CXCL9 in Cardiac Allograft Vasculopathy Am. J. Pathol., October 1, 2002; 161(4): 1307 - 1313. [Abstract] [Full Text] [PDF]
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Y. Hu, F. Davison, B. Ludewig, M. Erdel, M. Mayr, M. Url, H. Dietrich, and Q. Xu Smooth Muscle Cells in Transplant Atherosclerotic Lesions Are Originated From Recipients, but Not Bone Marrow Progenitor Cells Circulation, October 1, 2002; 106(14): 1834 - 1839. [Abstract] [Full Text] [PDF]
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A. M. Scheule, G. J. Zimmerman, J. K. Johnston, A. J. Razzouk, S. R. Gundry, and L. L. Bailey Duration of Graft Cold Ischemia Does Not Affect Outcomes in Pediatric Heart Transplant Recipients Circulation, September 24, 2002; 106(12_suppl_1): I-163 - I-167. [Abstract] [Full Text] [PDF]
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T. Wang, C. Dong, S. C. Stevenson, E. E. Herderick, J. Marshall-Neff, S. S. Vasudevan, N. I. Moldovan, R. E. Michler, N. R. Movva, and P. J. Goldschmidt-Clermont Overexpression of Soluble Fas Attenuates Transplant Arteriosclerosis in Rat Aortic Allografts Circulation, September 17, 2002; 106(12): 1536 - 1542. [Abstract] [Full Text] [PDF]
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S. C. Stoica, M. Goddard, and S. R. Large The endothelium in clinical cardiac transplantation Ann. Thorac. Surg., March 1, 2002; 73(3): 1002 - 1008. [Abstract] [Full Text] [PDF]
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Y. Furukawa, P. Libby, J. L. Stinn, G. Becker, and R. N. Mitchell Cold Ischemia Induces Isograft Arteriopathy, but Does Not Augment Allograft Arteriopathy in Non-Immunosuppressed Hosts Am. J. Pathol., March 1, 2002; 160(3): 1077 - 1087. [Abstract] [Full Text] [PDF]
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S. Sartore, A. Chiavegato, E. Faggin, R. Franch, M. Puato, S. Ausoni, and P. Pauletto Contribution of Adventitial Fibroblasts to Neointima Formation and Vascular Remodeling: From Innocent Bystander to Active Participant Circ. Res., December 7, 2001; 89(12): 1111 - 1121. [Abstract] [Full Text] [PDF]
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Z. Qian, R. Gelzer-Bell, S.-x. Yang, W. Cao, T. Ohnishi, B. A. Wasowska, R. H. Hruban, E. R. Rodriguez, W. M. Baldwin III, and C. J. Lowenstein Inducible Nitric Oxide Synthase Inhibition of Weibel-Palade Body Release in Cardiac Transplant Rejection Circulation, November 6, 2001; 104(19): 2369 - 2375. [Abstract] [Full Text] [PDF]
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S. C. Stoica, D. K. Satchithananda, J. Dunning, and S. R. Large Two-decade analysis of cardiac storage for transplantation Eur. J. Cardiothorac. Surg., October 1, 2001; 20(4): 792 - 798. [Abstract] [Full Text] [PDF]
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H. Tsutsui, K. M. Ziada, P. Schoenhagen, A. Iyisoy, W. A. Magyar, T. D. Crowe, J. D. Klingensmith, D. G. Vince, G. Rincon, R. E. Hobbs, et al. Lumen Loss in Transplant Coronary Artery Disease Is a Biphasic Process Involving Early Intimal Thickening and Late Constrictive Remodeling: Results From a 5-Year Serial Intravascular Ultrasound Study Circulation, August 2, 2001; 104(6): 653 - 657. [Abstract] [Full Text] [PDF]
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U. Sechtem Do heart transplant recipients need annual coronary angiography? Eur. Heart J., June 1, 2001; 22(11): 895 - 897. [PDF]
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J. Li, X. Han, J. Jiang, R. Zhong, G. M. Williams, J. G. Pickering, and L. H. Chow Vascular Smooth Muscle Cells of Recipient Origin Mediate Intimal Expansion after Aortic Allotransplantation in Mice Am. J. Pathol., June 1, 2001; 158(6): 1943 - 1947. [Abstract] [Full Text] [PDF]
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K. S. Kim, M. D. Denton, A. Chandraker, A. Knoflach, R. Milord, A. M. Waaga, L. A. Turka, M. E. Russell, R. Peach, and M. H. Sayegh CD28-B7-Mediated T Cell Costimulation in Chronic Cardiac Allograft Rejection : Differential Role of B7-1 in Initiation versus Progression of Graft Arteriosclerosis Am. J. Pathol., March 1, 2001; 158(3): 977 - 986. [Abstract] [Full Text] [PDF]
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E. Andriambeloson, M. Bigaud, E. O. Schraa, T. Kobel, V. Lobstein, C. Pally, and Hans-Gunter Zerwes Endothelial Dysfunction and Denudation in Rat Aortic Allografts Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 67 - 73. [Abstract] [Full Text] [PDF]
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C. A. Slachta, V. Jeevanandam, B. Goldman, W. L. Lin, and C. D. Platsoucas Coronary Arteries from Human Cardiac Allografts with Chronic Rejection Contain Oligoclonal T Cells: Persistence of Identical Clonally Expanded TCR Transcripts from the Early Post-Transplantation Period (Endomyocardial Biopsies) to Chronic Rejection (Coronary Arteries) J. Immunol., September 15, 2000; 165(6): 3469 - 3483. [Abstract] [Full Text] [PDF]
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S. Fateh-Moghadam, W. Bocksch, A. Ruf, T. Dickfeld, M. Schartl, G. Pogatsa-Murray, R. Hetzer, E. Fleck, and M. Gawaz Changes in Surface Expression of Platelet Membrane Glycoproteins and Progression of Heart Transplant Vasculopathy Circulation, August 22, 2000; 102(8): 890 - 897. [Abstract] [Full Text] [PDF]
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H. Holschermann, R. M. Bohle, H. Schmidt, H. Zeller, L. Fink, U. Stahl, H. Grimm, H. Tillmanns, and W. Haberbosch Hirudin Reduces Tissue Factor Expression and Attenuates Graft Arteriosclerosis in Rat Cardiac Allografts Circulation, July 18, 2000; 102(3): 357 - 363. [Abstract] [Full Text] [PDF]
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G. G. Miller, S. F. Davis, J. B. Atkinson, D. B. Chomsky, P. Pedroso, V. S. Reddy, D. C. Drinkwater, X.-M. Zhao, and R. N. Pierson Longitudinal Analysis of Fibroblast Growth Factor Expression After Transplantation and Association With Severity of Cardiac Allograft Vasculopathy Circulation, December 14, 1999; 100(24): 2396 - 2399. [Abstract] [Full Text] [PDF]
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C. H. Spes, V. Klauss, H. Mudra, S. D. Schnaack, A. R. Tammen, J. Rieber, U. Siebert, K.-H. Henneke, P. Uberfuhr, B. Reichart, et al. Diagnostic and Prognostic Value of Serial Dobutamine Stress Echocardiography for Noninvasive Assessment of Cardiac Allograft Vasculopathy : A Comparison With Coronary Angiography and Intravascular Ultrasound Circulation, August 3, 1999; 100(5): 509 - 515. [Abstract] [Full Text] [PDF]
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M. Schwaiblmair, W. v. Scheidt, P. Uberfuhr, B. Reichart, and C. Vogelmeier Lung Function and Cardiopulmonary Exercise Performance After Heart Transplantation: Influence of Cardiac Allograft Vasculopathy Chest, August 1, 1999; 116(2): 332 - 339. [Abstract] [Full Text] [PDF]
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R. Hullin, F. Asmus, A. Ludwig, J. Hersel, and P. Boekstegers Subunit Expression of the Cardiac L-Type Calcium Channel Is Differentially Regulated in Diastolic Heart Failure of the Cardiac Allograft Circulation, July 13, 1999; 100(2): 155 - 163. [Abstract] [Full Text] [PDF]
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H. Holschermann, R. M. Bohle, H. Zeller, H. Schmidt, U. Stahl, L. Fink, H. Grimm, H. Tillmanns, and W. Haberbosch In Situ Detection of Tissue Factor within the Coronary Intima in Rat Cardiac Allograft Vasculopathy Am. J. Pathol., January 1, 1999; 154(1): 211 - 220. [Abstract] [Full Text] [PDF]
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