Download cardiac allograft vasculopathy: background and recent advances

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CARDIAC ALLOGRAFT VASCULOPATHY:
BACKGROUND AND RECENT ADVANCES*
—
C
Jon A. Kobashigawa, MD†
ABSTRACT
Coronary artery disease in the transplanted
heart, also known as cardiac allograft vasculopathy (CAV), is a major cause of late mortality
after transplantation. A variety of immune and
nonimmune factors contribute to the pathogenesis. Intravascular ultrasonography (IVUS) is the
most sensitive method for detecting early CAV;
first-year IVUS results can predict 5-year outcomes after transplantation. Optimal prophylaxis
is not established, but several studies now indicate that the proliferation signal inhibitors (eg,
sirolimus and everolimus) and the statins (eg,
pravastatin) help reduce development of CAV;
mycophenolate mofetil, antihypertensives, vitamins C and E, and ganciclovir may also reduce
the risk of this posttransplant complication. For
those patients with established CAV, revascularization with angioplasty offers effective palliative
therapy. This article reviews the pathogenesis,
diagnosis, and treatment options for CAV.
(Adv Stud Med. 2008;8(6):189-195)
*Based on a presentation by Dr Kobashigawa at a
roundtable held in Parsippany, New Jersey, on February 9,
2008.
†Clinical Professor of Medicine and Chief, Division of
Clinical Faculty Medicine, The David Geffen School of
Medicine, University of California at Los Angeles; Medical
Director, Heart Transplant Program, Los Angeles, California.
Address correspondence to: Jon A. Kobashigawa, MD,
Clinical Professor of Medicine and Chief, Division of
Clinical Faculty Medicine, The David Geffen School of
Medicine, University of California at Los Angeles (UCLA),
100 UCLA Medical Plaza Building, #630, Los Angeles, CA
90095. E-mail: [email protected].
Johns Hopkins Advanced Studies in Medicine
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ardiac allograft vasculopathy (CAV) is a
major factor limiting long-term survival
after cardiac transplantation. Detectable
in more than 50% of patients at 10 years
after transplantation, early CAV (diagnosed within the first year after transplantation) is a
powerful predictor of 5-year mortality (relative risk =
2.06, 95% confidence interval, 1.57–2.70, P <.0001).1
This chronic complication is believed to be immune
mediated but nonimmune factors are also of importance. Current therapies are not effective and can, at
best, only slow the progression of CAV. This article
will describe our current understanding of CAV
pathogenesis, explain the potential value of intravascular ultrasound (IVUS) in predicting long-term outcomes and guiding therapy, and outline current
options for medical and surgical treatment.
PATHOGENESIS
The unique accelerated form of coronary artery
disease known as CAV starts when ischemia causes
injury to the donated organ’s endothelial cells. In
response, both immune and nonimmune factors act
on the endothelium, initiating a cascade of further
immunologic responses. Eventually, upregulation of
complement, inflammatory mediators, and cytokines
lead to the development of full CAV. A variety of factors—including the use of immunosuppressive medications, such as cyclosporine and corticosteroids—are
now thought to contribute to endothelial cell injury
and ultimately to the intimal hyperplasia that is characteristic of CAV (Figure 1).2
Although CAV exhibits similarities to the classic or
“native vessel” atherosclerosis (eg, leukocyte infiltration, cytokine production, extracellular matrix accumulation, lipid buildup, intimal smooth muscle
migration, and endothelial dysfunction), these diseases
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Figure 1. Proposed Mechanisms in the
Development of Allograft Vasculopathy
Acute rejection
Cyclosporine/corticosteroids
Ischemic time
Reperfusion
Endothelial
Cell Injury
Viruses (CMV)
Hyperlipidemia
Donor age
Hypertension
Intimal hyperplasia (allograft
vasculopathy)
CMV = cytomegalovirus.
Reprinted with permission from Kobashigawa. Curr Control Trials
Cardiovasc Med. 2000;1:166-171.2
are distinct from one another—perhaps mostly because
of the underlying immunologic trigger in the allogeneic
setting that confers a more diffuse and concentric distribution, in addition to a slightly altered lesion constitution (ie, more inflammation or intact internal elastic
lamina).3,4 Whereas immunologic factors clearly play a
role in CAV development, the exact contribution of
acute rejection to CAV pathophysiology and graft dysfunction remains under investigation. Smoldering cellular rejection, defined as a high first-year average biopsy
score, has been well established as a significant risk factor
for CAV.5,6 More recently, researchers have also documented that severe hemodynamic-compromising rejection, which is mostly humorally mediated, also appears
to be a prime risk factor in CAV and death.7
Although coronary angiography remains the most
widely used screening test for vascular disease, this
technique highlights only the luminal diameters and
therefore, often misses the intimal thickening associated with early CAV. This is because the coronary artery
in CAV often dilates in a compensatory response to
the thickening. In addition, because early CAV tends
to appear diffusely throughout the entire coronary tree
rather than in more intense focal lesions, angiography
may also tend to obscure any narrow points of constriction. This inability to detect early CAV is critical
in transplanted patients with denervated hearts
because these patients fail to display the classic accompanying warning signs of angina.
Because it provides a cross-sectional image of the
wall structure itself rather than just the lumen, IVUS
offers a potentially more sensitive technique for detecting CAV than angiography. As shown in Figure 2,
IVUS often reveals intimal thickening that might be
missed by angiography. Objective measurement of the
Figure 2. Comparison of Angiography and IVUS in
Detecting Intimal Thickening with Compensatory
Dilatation
DIAGNOSIS
Despite its poor inherent sensitivity, the coronary
angiogram has long been considered the gold standard
for diagnosing CAV. Dobutamine stress echocardiography is the most sensitive noninvasive alternative, detecting CAV with 92% sensitivity and 86% specificity versus
angiography.8 Other noninvasive tests that have been
compared directly to coronary angiography include single-photon emission computed tomography (CT) with
89% sensitivity and 71% specificity,9 and multidetector
CT with 86% sensitivity and 99% specificity.10
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On the left, coronary angiography suggests minimal or no luminal narrowing; evaluation of same patient with IVUS at distal point (lower right) also
shows an open artery; IVUS imaging at proximal point (upper right) shows
an identical luminal diameter but also reveals a large crescent area within
the right side of the vessel wall that represents significant intimal thickening. IVUS has detected vasculopathy with compensatory dilatation that
would have been missed by angiography alone. (Note: the small white circle in the center of the IVUS image is a catheter artifact.)
IVUS = intravascular ultrasound.
Courtesy of Tuzcu EM and Starling RC, Department of Cardiovascular
Medicine, Cleveland Clinic Heart and Vascular Institute, Cleveland, OH.
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intima with IVUS has now been used to screen for CAV
in large populations. One large study (N = 262) found
more than 50% of patients to have vasculopathy by
IVUS as soon as 1 year after transplantation—more than
5 times the rate of luminal irregularities found angiographically in the same patients.11 Although IVUS studies using different thickness thresholds to define CAV
have produced different results, the superior sensitivity
of ultrasound is clear and the potential value of early
IVUS results in predicting long-term morbidity and
mortality has now been established.12,13
In one of these validation studies, researchers from
several heart centers reviewed IVUS data from 125
patients who had been transplanted before 1998.12 The
IVUS examinations had been performed 4 to 6 weeks
after transplantation and then again at 1 year after the
surgery. Patients were separated into 2 groups: those
with first-year maximal intimal thickness (MIT) at or
above 0.5 mm and those with MIT lower than 0.5
mm. The prognostic significance of IVUS findings
were tested by analyzing their associations with 5-year
outcome data abstracted from the medical records.
The results showed that patients at or above the
0.5-mm cutoff had a higher incidence of eventual
death or graft loss (20.8% vs 5.9%, P = .007); more
nonfatal major adverse cardiac events and/or death or
graft loss (45.8% vs 16.8%, P = .008); and more newly
occurring angiographic luminal irregularities (65.2%
vs 32.6%, P = .004). This study indicates that firstyear IVUS data are a surrogate marker for 5-year outcomes after heart transplantation. As discussed next,
some newer immunosuppressive agents appear to
diminish CAV, and therefore, this study also implies
that first-year IVUS data may predict longer-term outcomes with these agents after transplantation.
to completely prevent or directly reverse development and progression of the disease process. Most
current therapies are aimed at specific elements of
suspected pathogenesis, such as those outlined in
Figure 1.2 Selected studies focused on prevention of
CAV—including several that have employed IVUS—
are discussed here.
In terms of antihypertensive therapy, one randomized study of 104 heart transplant patients showed that
the calcium channel blocker diltiazem led to a greater
average coronary luminal diameter at 1 to 2 years versus controls.14 Another study in 32 transplant patients
showed that calcium channel blockers and/or
angiotensin-converting enzyme inhibitors led to
reduced IVUS intimal thickness at 1 year versus
untreated controls.15
Antioxidants also may reduce development of
CAV. In one study, 40 heart transplant patients (0–2
years postoperative) were randomized to vitamin C
500 mg twice a day plus vitamin E 400 IU twice a day
or to placebo for 1 year.16 Over this period, the IVUS
intimal index (plaque area divided by vessel area)
increased by 8% in the placebo group versus 0.8% in
the treatment group (P = .008) leading to the conclusion that supplementation with vitamins C and E
retards early progression of transplant-associated coronary atherosclerosis.
Cytomegalovirus (CMV) is associated with development of CAV,17 most likely through direct and indirect cell endothelial damage. Specific mechanisms may
involve upregulation of proinflammatory adhesion
molecules in CMV-infected endothelial cells and
Table. Medical Therapies to Treat CAV
TREATMENT APPROACHES
In addition to improved handling, storage, and
transport of grafts, the main approaches for managing
CAV include modification of cardiovascular risk factors (such as control of hypertension and diabetes, cessation of smoking, and weight loss), medical therapies,
revascularization, and retransplantation.
MEDICAL THERAPIES
Several studies have evaluated the short-term
impact of medical therapies on CAV (Table).
Unfortunately, none of these agents have been shown
Johns Hopkins Advanced Studies in Medicine
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• Antihypertension agents
– Calcium channel blockers
– Angiotensin-converting enzyme inhibitors
• Antioxidants
– Vitamins C and E
• Antibiotics
– Ganciclovir
• Immunosuppression
• Lipid-lowering agents
– 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (statins)
CAV = cardiac allograft vasculopathy.
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patients in the everolimus group had less CAV and
fewer major adverse cardiac events, including revascularizations, compared with those in the azathioprine
group over this long follow-up period.
One single-center study (N = 46) also found that
sirolimus may slow disease progression in patients with
existing CAV.29 After discovery of CAV at routine
catheterization 3 to 5 years posttransplantation,
patients were randomized to sirolimus or continued
current immunosuppression. Two years later, only 3 of
22 patients taking sirolimus had achieved the primary
end point (ie, death, need for revascularization,
myocardial infarction, and >25% worsening of
catheterization score) versus 14 of 24 patients in the
control group (P <.001).
Finally, in terms of immunosuppression, note that
photopheresis, a procedure in which pheresed white
blood cells are treated with 8-methoxy-psoralen and
given ultraviolet irradiation and then reinfused, has
been shown in a small study to cause an unspecified
immunomodulating effect that decreased CAV.30
The use of 3-hydroxyl-3-methylglutaryl coenzyme
reductase inhibitors (statins) has also demonstrated
benefit in transplant patients. In a study of 97 heart
transplant patients randomized to pravastatin or no
pravastatin, not only did the active treatment group
have lower mean cholesterol (193 ± 36 mg/dL vs 248
Figure 3. Impact of Everolimus Versus Azathioprine
on CAV: Percentage of Patients with Change in
IVUS MIT ≥0.5 mm at 12 Months
P = .045
60
P = .01
50
Patients, %
cytokines in infected T cells18; inhibition of apoptosis
in infected smooth muscle cells19; and elevations in
antiendothelial cell antibodies in infected individuals.20 Retrospective studies indicate that prophylaxis
with ganciclovir with or without CMV hyperimmune
globulin early after transplantation may reduce the risk
of CAV.21-23
In terms of immunosuppressive agents, 3 multicenter trials and 1 single-center trial provide evidence
suggesting that specific agents slow CAV progression.
In a multicenter randomized trial involving 650 heart
transplant patients, those receiving mycophenolate
mofetil (MMF) had clear survival and rejection benefits versus those receiving azathioprine but there was
no significant difference in the baseline-to-1-year
IVUS scores between treatment groups.24 However,
when the 10 IVUS images from each patient were
reanalyzed by matching site-to-site comparisons rather
than averaging the 10 readings (which can mask the
progression of intimal thickening at any one vessel
site), patients in the MMF group had significantly less
progression of first-year intimal thickening.25 Only
23% of those in the MMF group had a first-year
change in MIT at or above 0.3 mm versus 43% of
those in the azathioprine group (P = .005).
In a multicenter randomized trial (N = 136) comparing sirolimus to azathioprine, rejection rates were
lower and serum creatinine higher in the sirolimus
groups at 6 months.26 No differences in mortality were
noted at 1 year. Results from IVUS taken at 6 weeks,
6 months, and 2 years showed that CAV had progressed markedly in azathioprine-treated patients. By
comparison, sirolimus was associated with a significant
absence of progression in intimal and medial proliferation at 6 months and 2 years.
The other proliferation inhibitor, everolimus, was
also evaluated recently for its impact on CAV. In this
randomized multicenter trial (N = 634), the combined
primary end point, including rejection, graft loss, and
death, was significantly lower in the everolimus group
versus the azathioprine group.27 The 12-month IVUS
results showed that the average MIT increase and the
overall incidence of vasculopathy were significantly
less in the everolimus groups versus the azathioprine
group (Figure 3).27 A 4-year follow-up of this study
showed that everolimus led to significantly less efficacy failure (ie, biopsy-proven rejection, graft loss, and
death) (P <.05) and significantly less intimal thickening (P ≤.01) over this period.28 In addition, those
40
30
20
10
0
35.7%
30.4%
52.8%
Everolimus 1.5 mg
(n = 70)
Everolimus 3 mg
(n = 69)
Azathioprine
(n = 72)
Pairwise comparison with Wilcoxon’s rank sum test.
CAV = cardiac allograft vasculopathy; IVUS = intravascular ultrasound;
MIT = maximal intimal thickness.
Adapted with permission from Eisen et al. N Engl J Med. 2003;349:847-858.27
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± 49 mg/dL, P <.001) at 1 year, they also demonstrated less frequent cardiac rejection accompanied by
hemodynamic compromise (3 vs 14 patients, P =
.005), better survival (94% vs 78%, P = .025), and a
lower incidence of CAV as determined by angiography
and at autopsy (3 vs 10 patients, P = .049).31 In an
IVUS substudy, intimal thickness showed 50% less
progression in the pravastatin group (P <.04). A 10year follow-up study of these patients showed that the
early benefits associated with pravastatin treatment
persisted in terms of survival and lower incidence of
CAV (Figure 4).32 Ten-year survival in the statin group
was 68% versus 48% in the control group (P = .028).
coronary artery bypass after heart transplantation have
been generally poor, with small studies indicating high
rates of perioperative36 and 1-year mortality.37
Retransplantation is the only effective manner of
therapy for severe CAV. Rates of survival are acceptable
if retransplantation is performed after the first year and
if patients with acute rejection are excluded.38 Registry
data indicate that 1-year patient survival rates reach
70% to 80% in patients retransplanted after 12 to 24
months.38 However, the ethical dilemma of retransplantation in these patients is considerable due to the
scarcity of donor organs.
CONCLUSIONS
CORONARY REVASCULARIZATION AND RETRANSPLANTATION
Percutaneous transluminal coronary angioplasty is
used extensively as palliative treatment for CAV. In a single-center study of 29 heart transplant recipients, 50 of
53 lesions (94.3%) were successfully opened (<50%
stenosis) with angiography; restenosis (≥50%) was seen
at 14 of 43 (32.5%) sites at 6 months.33 In a study of
drug-eluting stents, there was a trend toward lower
restenosis rates (2 of 13, 15%) compared to bare metal
stents (20 of 65, 31%) at 40 months.34 And in a study of
62 transplant patients who received angioplasty for CAV,
freedom from restenosis (seen in 81% of patients at 3
months and 57% at 6 months), the multivariate predictors of success were use of stents and high antiproliferative immunosuppressant doses.35 Outcomes with
Freedom from CAV/death, %
Figure 4. Decade-Long Effect of Statins on Survival
and/or Freedom from CAV
100
90
80
70
60
50
40
30
20
10
0
Pravastatin (n = 47)
P = .009
Control (n = 50)
0
1
2
3
4
5
6
7
8
9
10
Year
CAV = cardiac allograft vasculopathy.
Reprinted with permission from Kobashigawa et al. J Heart Lung Transplant.
2005;24:1736-1740.32
Johns Hopkins Advanced Studies in Medicine
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The pathogenesis of CAV includes immune and
nonimmune factors. First-year IVUS data can provide an early marker for long-term outcomes. The
proliferation inhibitors, sirolimus and everolimus,
and the statins show clinical benefit in preventing
CAV. For patients with existing CAV, revascularization is effective palliative therapy and retransplantation offers a more definitive solution but is limited
by organ shortages.
DISCUSSION
Dr Eisen: Diagnosing transplant coronary disease
is complicated. At Hahneman, the procedure we use
most frequently, despite its flaws, is coronary angiography. Usually, we do not employ IVUS unless it is
part of a clinical trial because it is not reimbursed. On
occasion, we convince payers to pay for IVUS in
selected patients. For patients at high risk, we will
sometimes perform either dobutamine stress echocardiography or pharmacologic stress testing with nuclear
imaging. But noninvasive tests are limited, thus we
depend on angiography.
Dr Rogers: We take a similar approach at Duke,
with annual screens primarily with coronary angiography for the first 5 years and then less frequent angiography after that. In years without angiography, we
typically perform a pharmacologic stress test, usually
dobutamine stress echocardiography.
Dr Eisen: Our angiographers use vasodilators, usually intracoronary nitroglycerin, as part of the standard
procedure but we do not attempt quantitation because
it is so much more time consuming and requires special expertise.
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Dr Russell: Let me ask a radical question: Why do
we cath people at all? There is increasing evidence that
patients do not benefit greatly from stenting asymptomatic lesions. In fact, changing therapy rarely alters
disease progression and, at any rate, we rarely act until
the ejection fraction drops.
Dr Kobashigawa: In certain patients, we do pick
up isolated lesions amenable to angioplasty. But it is
true that we still need a randomized trial of non-left
main, nonproximal left ventricular assist device lesions
to see if angioplasty has a benefit. The COURAGE
trial [Clinical Outcomes Utilizing Revascularization
and Aggressive Drug Evaluation]39 showed no benefit
here, but we have not yet tested this in cardiac transplant patients. The outcome might be similar in the
transplant setting because the disease process is diffuse.
Studies show that cardiac transplant patients with
restenosis after angioplasty have further progression
over the rest of the coronary arteries—that is, it is a
homogeneous disease.
Dr Eisen: The other factor that might make it
imperative to identify those with coronary disease is the
preliminary evidence presented by Dr Kobashigawa29
showing that altering immunosuppression, in this case
with sirolimus, may favorably affect outcomes. We need
a much larger clinical trial with either sirolimus or
everolimus to build on this Mancini data.
Dr Rogers: Statins have immunomodulatory effects
and improve long-term outcomes in transplant patients.
But are all statins alike in heart transplantation?
Dr Kobashigawa: I believe it is a class effect in
transplant and nontransplant populations. We have
found that various statins depress natural killer cell
(NKC) activity to similar degrees but we have also found
that the immunomodulatory impact on NKCs becomes
even more striking when the statin is combined with a
calcineurin inhibitor. This occurs because calcineurin
inhibitors increase statin levels by approximately 20-fold
while, conversely, the statin increases the enzyme
inhibitor concentration levels by approximately 8-fold.
This boosts the bioactivity of the drug. That is why the
immunomodulatory effect of statins is magnified in
transplant patients compared to nontransplant patients
on statins but not cyclosporine or tacrolimus. It is also
why opportunistic infections are not a problem in those
millions of individuals on statins.
Dr Rogers: Does this change in pharmacokinetics
also account for the increased statin-related side
effects seen in this population—effects such as
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increased muscle pathology, myalgias, and elevated
creatinine kinase levels?
Dr Kobashigawa: Yes. But it also depends on the
statin’s lipophilicity and hydrophilicity. Hydrophilic
drugs, such as pravastatin and rosuvastatin, have a lower
incidence of myalgias and rhabdomyolysis. With simvastatin, especially when you go from 5 mg or 10 mg up to
20 mg, which is an average dose, there are more problems
with myositis. This is less of a problem with pravastatin.
Dr Conte: How do you manage a patient who
receives a donor heart with a low level of native coronary disease? Other than considering a back table
bypass graft on an organ before implantation, are there
any management differences?
Dr Eisen: We might consider sirolimus, the currently available proliferation signal inhibitor (PSI).
The potential problem with sirolimus in these patients
is wound healing, thus we might start the PSI approximately 3 months out once the wound has healed.
However, there are no data on this approach.
Dr Kobashigawa: This is a common problem. The
registry data show that both older age and preexisting
coronary disease in the donor are risk factors for the
development of transplant vasculopathy. Up to 80% of
the older general population will show intimal thickening on IVUS—and that is about what you will see
on transplant patients at baseline or 1 year.
Dr Eisen: Even the younger donor hearts—and keep
in mind older is defined as over 40 years—are at higher
risk for developing de novo diseases after transplant.
Dr Rogers: Are you using antioxidants?
Dr Kobashigawa: Yes. We routinely use vitamin C
and vitamin E based mainly on the IVUS data I discussed.16 There also appears to be a beneficial interaction of these agents in combination with the
calcineurin inhibitors. We do not yet know if the other
antioxidant agents, such as coenzyme Q10 or vitamin
A, will be helpful.
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