REVIEW ARTICLE

Cardiac Allograft Vasculopathy

Advances in Diagnosis
Qiangjun Cai, MD, Umamahesh C. Rangasetty, MD, Alejandro Barbagelata, MD, Kenichi Fujise, MD,
and Michael M. Koerner, MD, PhD

Abstract: Cardiac allograft vasculopathy (CAV), characterized by diffuse

intimal thickening and luminal narrowing in the arteries of the allograft, is
the leading cause of morbidity and mortality in cardiac transplant recipients.
Many transplant centers perform routine annual surveillance coronary angiography. However, angiography can underdiagnose or miss CAV due to its
diffuse nature. Intravascular ultrasound (IVUS) is more sensitive than angiography. IVUS provides not only accurate information on lumen size, but
also quantification of intimal thickening, vessel wall morphology, and
composition. IVUS has evolved as a valuable adjunct to angiography and the
optimal diagnostic tool for early detection. Noninvasive testing such as
dobutamine stress echocardiography and nuclear stress test have shown
considerable accuracy in diagnosing significant CAV. Computed tomographic imaging and cardiac magnetic resonance imaging are promising new
modalities but require further study. This article reviews the diagnostic
methods that are currently available.
Key Words: cardiac allograft vasculopathy, diagnosis, angiography,
intravascular ultrasound, noninvasive testing
(Cardiology in Review 2011;19: 30 35)

ardiac transplantation (HTx) is the definitive treatment for

eligible patients with end-stage heart failure. More than 5000
HTx are performed annually worldwide.1 Cardiac allograft vasculopathy (CAV) and graft failure (most likely undetected CAV) are
the leading cause of death in patients who survive the first year after
HTx, accounting for 32% of deaths 5 years postoperatively.1 The
incidence of CAV varies depending on the techniques used to detect
it. By angiography, CAV is detectable in 52% of survivors 10 years
after HTx.1 The etiology of CAV, although not completely understood, likely involves an interplay between immunologic, infectious,
growth factors, and classic risk factors.25

CHARACTERISTICS OF CARDIAC ALLOGRAFT

VASCULOPATHY

DIAGNOSIS OF CARDIAC ALLOGRAFT

VASCULOPATHY
Importance of Early Diagnosis
The diagnosis of CAV is challenging because of cardiac
denervation and the diffuse nature of the disease. Early CAV is
clinically silent, and ischemia is usually not evident until the disease
is far advanced. Because of the lack of early clinical symptoms,
patients with CAV typically present late with silent myocardial
infarction, loss of allograft function, or sudden death.15 Owing to the
diffuse nature of vasculopathy, conventional therapeutic approaches
including percutaneous coronary intervention and coronary artery
bypass grafting are optional only late in the course and are not
always successful.11,16 18 Cardiac retransplantation is often the last
resort; however, this is not an ideal choice because of the limited
donor pool. Therefore, it is important to identify asymptomatic
patients early during the development of CAV by screening studies.19 One of the goals of CAV screening is to detect focal disease
which is amenable to some form of intervention. The more important goal is the detection of diffuse disease which is prognostically
relevant.20,21
During the past few years, progress has been made in the
understanding of CAV pathogenesis and advances have occurred in
the diagnosis of CAV. This review focuses on the diagnostic
methods that are currently available.

Angiography

Unlike native atherosclerotic coronary artery disease (CAD)

which is usually a focal, eccentric stenosis of epicardial coronary
vessels, CAV is characterized initially by diffuse intimal thickening
in both the epicardial and intramyocardial arteries of the transplanted heart, and later by luminal narrowing and occlusion of small
arteries. Changes in the intima have been demonstrated as early as
3 months after transplantation.6 Constrictive remodeling further
contributes to the narrowing of vessels later in the disease process.79 Rapid progression of intimal thickening in the first year after
From the Division of Cardiology, Department of Medicine, and Texas Transplant
Center, University of Texas Medical Branch, Galveston TX.
Correspondence: Michael M. Koerner, MD, PhD, Division of Cardiology, Department of Medicine and Texas Transplant Center, University of Texas
Medical Branch, 301 University Blvd, JSA 5.106E, Galveston TX, 77555.
E-mail: mmkoerne@utmb.edu.
Copyright 2011 by Lippincott Williams & Wilkins
ISSN: 1061-5377/11/1901-0030
DOI: 10.1097/CRD.0b013e3181fbde2f

30 | www.cardiologyinreview.com

HTx, as determined by intravascular ultrasound (IVUS) analysis, is

a powerful predictor of future cardiac events. The diffuse and
progressive nature of CAV is one of the factors responsible for the
poor outcome of interventional therapies.10,11 Early after HTx, focal
donor-transmitted epicardial intimal thickening is detectable.12
However, pre-existing donor disease does not accelerate the progression of CAV or affect the long-term survival.13,14

Coronary angiography remains the principal screening tool

for CAV in most centers. It can guide therapy, help determine
prognosis and predict adverse events. The Stanford classification
system has been developed to describe lesion morphologies commonly seen at angiography in HTx recipients.2,22 In this classification system, CAV can range from discrete atherosclerosis to concentric arterial obliteration. Angiography detects the presence of
vasculopathy in 10% to 20% of transplant recipients at 1-year
follow-up, rising 10% per year to 50% at 5 years.23 Once mild
disease is identified angiographically, the likelihood of progression
to severe CAV within 5 years is increased from 9% to 19%.24 The
presence of significant angiographic stenosis conveys a poor prognosis. In patients with at least 1 focal stenosis of 40%, survival
was 67% at 1 year, 44% at 2 years, and 17% at 5 years. With 3
vessels involved, survival was 13% at 2 years.25 Patients with a
moderate coronary lesion (30% and 60% stenosis) who showed
angiographic progression 1 year later experienced higher rates of
revascularization and sudden death.26 The lack of progression at

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Cardiology in Review Volume 19, Number 1, January/February 2011

1 year identifies a group who are likely to remain free of clinical

events through 6 years of follow-up.26,27

Limitations of Angiography
There is no compromise in luminal diameter in early CAV
due to vascular remodeling.28 Therefore, as a luminography which
measures luminal diameter, coronary angiography can underdiagnose or miss CAV.29 In addition, coronary angiography requires the
presence of normal neighboring arteries for comparison. However,
necropsy studies demonstrate that CAV usually involves the entire
coronary arterial tree, with no truly normal segment. Therefore,
angiograms should be interpreted serially as new and concentric
lesions may be missed on 1-time angiograms. Using IVUS and an
intimal thickness of 0.3 mm as the diagnosis of CAV, the positive
predictive value of coronary angiography was only 44%.30 32 This
has also been demonstrated by histopathological studies.33

Other Techniques Using Angiography

In HTx recipients followed up for 5 years, an increase in the
Thrombolysis in Myocardial Infarction frame count, which correlates with a decrease in the rate of resting coronary blood flow, was
observed in those who developed angiographic transplant vasculopathy.34 Measurement of coronary artery flow reserve may provide additional information about the presence and severity of
transplant vasculopathy.35 Patients with vasculopathy are more
likely to have reduced coronary artery flow reserve compared with
those without.36 Also, the use of quantitative myocardial blush grade
may help with the identification of early CAV in patients with
impaired perfusion reserve, but without angiographically-evident
atherosclerosis.37

Cardiac Allograft Vasculopathy

cess,7,9,39 which is similar to native atherosclerosis. A 5-year serial

IVUS study revealed that most of the intimal thickening occurred
during the first year after HTx. Changes in the EEM area showed a
biphasic response, consisting of early expansion and late constriction.39
Early lumen loss is primarily caused by intimal thickening, whereas late
lumen loss is caused by EEM area constriction. However, a subgroup of
patients with CAV experience early constrictive rather than expansive
remodeling of the EEM.9,50 The mechanisms determining early constrictive versus expansive remodeling are unknown, and the clinical
significance of this difference is uncertain.

Prediction of Cardiac Events

CAV is considered present when intimal thickness is 0.3
mm or when the sum of the intimal and medial thickness is 0.5
mm. Rapidly progressive CAV, defined as an increase of 0.5 mm
in maximal intimal thickness within the first year after HTx, was
associated with increased death or graft loss, myocardial infarction,
or need for revascularization.38,40,51,52 The IVUS-defined rapid
progression also correlated highly with future development of angiographic disease. With 0.6 mm intimal thickening, patients are
10 times more likely to experience a cardiac event.51 For those who
developed cardiac events, 62% of patients had normal angiograms.51
There was no significant difference in outcome in patients with and
without donor-transmitted lesions detected by IVUS. These data
demonstrate the ability of IVUS to identify a high-risk population in
the first year after HTx and underscore the importance of serial
ultrasound examinations. The prognostic value of a single IVUS
result by the Stanford scale to predict CAV has been validated. The
average times of onset of significant CAV were 4.1, 3.6, and 5.5
years for IVUS grade 2, 3, and 4, respectively.53 CAV did not
develop during follow-up in patients with IVUS grade 0 or 1.

Intravascular Ultrasound
In the past decade, IVUS has evolved as a valuable adjunct to
angiography, providing insights into the natural history and prognostic significance of allograft vasculopathy.29,38 41 This has significantly altered conventional paradigms in diagnosis and therapy.
Most clinical studies assessing new treatment regimens use IVUS to
evaluate the efficacy.20,42 44

Advantages of Intravascular Ultrasound

Angiography depicts only a 2-dimensional silhouette of the
lumen, whereas the penetrating nature of IVUS allows a high-resolution
image of the cross-section of the vessel, providing not only accurate
information on lumen size, but also quantification of intimal thickening,
vessel wall morphology, and composition.28,38 IVUS can detect occult
disease in angiographically normal sites and has emerged as the optimal
diagnostic tool for early detection. The presence of CAV has been
reported to be as high as 75% at 1 year after HTx, using IVUS, whereas
angiography detects disease in only 10% to 20% of patients.45,46 In the
early stage of vasculopathy, plaque burden measured by IVUS correlated with impairment of microvascular integrity when fractional flow
reserve and angiograms were normal.47 CAV severity can be classified
according to maximal intimal thickness and concentricity of involvement.30 Serial IVUS allows considerable statistical power to detect
small changes.

Natural History of Cardiac Allograft Vasculopathy by

Intravascular Ultrasound
IVUS has demonstrated that post-transplant remodeling of the
coronary arteries is a dynamic process. Coronary artery narrowing is
determined not only by an increase in intimal hyperplasia but also by
the direction of vascular remodeling.48,49 Most arteries affected by
intimal hyperplasia develop an expansion of the external elastic membrane (EEM) that preserves lumen area early in the remodeling pro 2011 Lippincott Williams & Wilkins

Analysis of Plaque CompositionVirtual Histology

Although IVUS is sensitive and allows earlier detection of
CAV, Grayscale IVUS has significant limitation in the evaluation
of plaque composition.54,55 Recent advances in spectral analysis of
IVUS radiofrequency data, known as virtual histology IVUS (VHIVUS), offers a novel technology to characterize plaque morphology
in vivo and quantitative evaluation of different plaque components.
VH-IVUS constructs tissue maps that classify plaque into the
following 4 major components: necrotic core, calcium, fibrous, and
fibrolipid. A significant correlation between VH-IVUS-derived
plaque components and time, donor age, and cardiovascular risk
factors has been found. The presence and proportion of necrotic core
was linked to older donor, male recipients, and patients with diabetes. Plaques assessed 24 months or less after HTx had low calcium
and necrotic core content but increased fibrous and fibrofatty components. The amount of necrotic core and the magnitude of calcification increased significantly from 24 months on, and such focal
unstable lesions were found in 7.2% of patients.56 Thin-cap fibroatheromas were detected only at 5 years and beyond.57 Necrotic core
volume 2.01 mm was associated with the need for revascularization. VH-IVUS is especially valuable for low-echogenic plaques
with mainly lipid or mixed composition.
On the basis of the VH-IVUS plaque characteristics, coronary
allograft plaque was divided into inflammatory (necrotic core and
dense calcium 30%) and noninflammatory plaque (necrotic core
and dense calcium 30%). The presence of inflammatory plaque is
associated with early recurrent rejection and higher subsequent
progression of CAV.58

Safety of Intravascular Ultrasound

The safety profile of IVUS is well documented. The rate of
complication such as transient spasm varies from 1% to 3%. The
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Cardiology in Review Volume 19, Number 1, January/February 2011

major complication rate such as dissection or vessel closure is

0.5%.59 62 There is concern that repeated intracoronary instrumentation itself might accelerate CAV by causing endothelial injury.
However, examination of vessels previously imaged by IVUS compared with noninstrumented vessels shows no accelerated progression of atheroma, regardless of the number of IVUS exams and
duration of follow-up. Therefore, serial IVUS imaging is a safe
method for the detection and surveillance of transplant CAD.59,63,64

Limitation of Intravascular Ultrasound

The physical size of the IVUS catheter is restricted to the larger
epicardial arteries, which leaves imaging of the secondary or tertiary
vessels technically impossible. The intimal index determined by IVUS
does not correlate with small artery disease by histological or immunohistochemical analysis.65 In addition, if only one of the major
epicardial vessels is imaged, which is the usual practice, a significant
amount of CAV will be missed.66 CAV was diagnosed in 58% of
patients in whom all 3 vessels were imaged at 1 year, compared with
27% in single-vessel imaging.66 Extra cost, lack of expertise, and
extensive postprocessing analysis are other drawbacks of IVUS that
limit its widespread use. IVUS measurements by manual planimetry
poorly correlate with computer-assisted analysis based on semiautomated border detection, with a variation over 10%.67

Noninvasive Testing
Because angiography and IVUS are invasive tests, they pose
increased risks for the patients. Noninvasive techniques for detecting
CAV are gaining acceptance in clinical practice, even though ischemia by functional testing does not usually occur until the disease is
advanced.

Exercise Electrocardiography
Few studies have looked at the role of exercise electrocardiography in the diagnosis of CAV. Limiting factors in the HTx
population, such as abnormal baseline electrocardiography, can
decrease the sensitivity of the test. Patients often are unable to
exercise to target heart rate. The sensitivity and specificity of supine
exercise testing for CAV were 21% and 77%, respectively, in 58
patients.68 By exercise treadmill testing, a specificity of 90% in 36
patients was reported.69 Its most important role is the assessment of
functional class and response to cardiac medications.

Echocardiography
Echocardiography has been tested in the HTx population with
varying techniques. Dobutamine stress echocardiography (DSE) for
assessment of wall motion and left ventricular function is the most
frequently used, and has a sensitivity of 70% to 80% for detecting
CAV compared with coronary angiography.70,71 When intimal
thickening by IVUS is taken as the gold standard, DSE shows
specificities of up to 88%.72,73 In a study of 109 transplant recipients
in whom yearly DSE was performed at the time of angiography and
IVUS, the sensitivity of 2-dimensional echocardiography was 57%
at rest and increased to 72% with DSE; the values were further
improved with concurrent M-mode analysis (72% and 85%, respectively). The sensitivity of DSE remains strong even when nonfocal
and nonsignificant stenotic disease is considered.71,74 A normal DSE
incorporating M-mode measurement of wall thickening predicts an
uneventful clinical course,73 suggesting an excellent negative predictive value. Serial deterioration during stress was associated with
an increased risk of events, with a relative risk of 7.3. Normal DSE
may allow for the safe postponement of surveillance angiography
after the first year. Moreover, a predictive value of DSE for development of future CAV and outcome has been described.73,75 Regional wall motion abnormalities may be present even in angio32 | www.cardiologyinreview.com

graphically normal graft arteries, suggesting that endothelial

dysfunction may account for these findings.76
The measurement of a lower coronary flow rate with contrastenhanced transthoracic echocardiography has demonstrated good
accuracy (89%) for detecting CAV, and is a reliable marker for
CAV-related major cardiac events.77,78 However, this may not be
assessable in all patients. The use of myocardial contrast echocardiography with dobutamine was moderately sensitive (70%) and
very specific (96%) for the presence of 50% angiographic stenosis.
However, multivessel disease was not well identified.77 Real-time
myocardial contrast echocardiography visual grading of myocardial
segments increased the accuracy of conventional DSE in the detection of significant CAV after HTx from 80% to 87%. This was
further increased to 90% by adding quantitative assessment of the
myocardial perfusion.79
The combined use of contrast-enhanced echocardiography
and adenosine-mediated hyperemia to assess coronary flow reserve
has shown promising results. In 73 patients at a mean of 8 years after
HTx, using a coronary flow reserve cutoff of 2 or less, the specificity
for angiographic CAV was 100%.80 With a cutoff of 2.7 or lower,
the specificity and sensitivity were 87% and 82%, respectively. A
coronary flow reserve of 2.6 or less was associated with a 3.1
relative risk of death, myocardial infarction, congestive heart failure,
or need for percutaneous intervention at a mean of 19 months.78 This
technique is new and further data are required.

Single-Photon Emission Computed Tomography

Myocardial single-photon emission computed tomography has a
high negative predictive value in screening for significant CAV.81,82
Earlier studies on thallium and dipyridamole showed sensitivities of
21% to 58% and specificities of 64% to 88%.67,82,83 The use of exercise
or dobutamine as a stressor increases the accuracy of thallium testing.84 86 In 47 patients at a mean of 34 months after HTx, a sensitivity
of 89% and a specificity of 71% were recorded. Importantly, all patients
with 6 segment reversible perfusion defects had angiographic CAV.
They also showed a correlation of increased cardiac death in those with
large reversible defects.
Recent trials are using newer tracers including sestamibi and
tetrofosmin.86 89 The sensitivity of nuclear imaging increases as the
burden of CAV increases, up to 100% with triple-vessel disease
using dobutamine tetrofosmin.88 Hacker et al found an increase in
cardiac events with any fixed or reversible defects on dobutamine
sestamibi at 12 months of follow-up.89 Using visual assessment,
they found a sensitivity and specificity of 90% and 72%, respectively, for prediction of events. Using exercise and dobutamine
tetrofosmin, the presence of abnormal perfusion was associated with
a risk ratio of 3.5 for predicting cardiac death.90

Computed Tomography
Computed tomographic angiography is a relatively new imaging modality for the diagnosis of CAD. Romeo et al reported a
sensitivity of 83% and a specificity of 95% for 16-slice multidetector
computed tomography (MDCT) for detection of more than 50%
angiographic stenosis and a negative predictive value of 95% at a
mean of 7.6 years after transplant.91 MDCT with adaptive multisegment reconstruction has a sensitivity and specificity of 86% and
99%, respectively, for stenoses greater than 50% in segments 1.5
mm on quantitative coronary angiography.92 Iyengar et al found a
good overall agreement of conventional catheter-based angiography
and 64-slice MDCT, with MDCT superior to identify nonobstructive
vessel wall disease.93 Strictly normal CT findings were associated
with no stenoses on angiography.91 The major drawbacks with the
routine use of MDCT after HTx include the high heart rate of
patients which might compromise imaging quality, contrast-induced
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Cardiology in Review Volume 19, Number 1, January/February 2011

nephropathy, and radiation.94,95 Compared with IVUS, the sensitivity, specificity, positive and negative predictive values for the
detection of CAV by dual source CT were 85%, 84%, 76%, and
91%, respectively. Dual source CT permits the investigation of HTx
recipients concerning the presence of CAV with good image quality
and high diagnostic accuracy.96
Electron-beam CT has also been studied for CAV. Knollmann
et al analyzed 112 post-HTx patients and found a sensitivity of 94%
and a specificity of 79%, when a calcium score of 55 was
compared with 50% angiographic stenosis.97 With IVUS comparison, sensitivity was 82% with a specificity of 97% for a calcium
score lower than 3 for the diagnosis of Stanford grade 4. However,
Ratliff et al were unable to find a satisfactory correlation between
electron-beam CT calcium scores and angiographic disease.98 This
is likely due to the erratic presence of calcium in transplant CAD.

5.

6.
7.

8.

9.

Magnetic Resonance Imaging

In a spectroscopic magnetic resonance imaging (MRI) study
looking at angiographic CAV, the presence of a ratio of phosphocreatine to adenosine triphosphate 1.59 was 100% sensitive and 72%
specific for the diagnosis of CAV.99 The lack of widespread familiarity
and expertise makes MRI spectroscopy in the HTx population only
investigational. With a sensitivity of 100% and specificity of 85%,
myocardial perfusion reserve as detected by MRI after adenosine
infusion has the potential to become an alternative to angiography for
routine surveillance.99 Magnetic resonance coronary angiography currently shows limited sensitivity for detecting CAV.100

Positron Emission Tomography

Recently, positron emission tomography (PET) has been
considered the gold standard noninvasive test for myocardial perfusion imaging. By quantification of the absolute myocardial blood
flow during stress and rest, the myocardial perfusion reserve can be
deduced to represent the epicardial arteries or microvascular dysfunction.101,102 For HTx recipients, myocardial perfusion reserve
measured by PET has been tested in only a few studies.103,104 Wu et
al found that plaque burden as determined by IVUS agrees well with
myocardial perfusion reserve, as assessed by PET in HTx recipients
with normal coronary angiography results.105

SUMMARY
There are no specific protocols as to the screening and
follow-up of CAV in HTx patients.106 Many centers perform routine
annual angiography immediately after the procedure and less frequently afterward. IVUS immediately and 1 year after HTx may
identify high-risk patients and aid in prognostic stratification. However, this technique should be considered only supplemental to
angiography. Noninvasive testing could modify this protocol, given
the encouraging results.107 Measurement of systemic markers of
inflammation, which has been associated with CAV determined by
IVUS or VH-IVUS, may play a complementary role.107 The surveillance intensity of coronary angiography might be designed
reasonably and safely on the basis of noninvasive monitoring.87
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