PET Imaging of Atherosclerotic Disease: Advancing Plaque Assessment from Anatomy to Pathophysiology
Curr Atheroscler Rep
PET Imaging of Atherosclerotic Disease: Advancing Plaque Assessment from Anatomy to Pathophysiology
Nicholas R. Evans 0 1 2
Jason M. Tarkin 0 1 2
Mohammed M. Chowdhury 0 1 2
Elizabeth A. Warburton 0 1 2
James H. F. Rudd 0 1 2
0 Division of Vascular and Endovascular Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus , Cambridge CB2 0QQ , UK
1 Division of Cardiovascular Medicine, University of Cambridge , Cambridge Biomedical Campus, Cambridge CB2 0QQ , UK
2 Department of Clinical Neurosciences, University of Cambridge , Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ , UK
Atherosclerosis is a leading cause of morbidity and mortality. It is now widely recognized that the disease is more than simply a flow-limiting process and that the atheromatous plaque represents a nidus for inflammation with a consequent risk of plaque rupture and atherothrombosis, leading to myocardial infarction or stroke. However, widely used conventional clinical imaging techniques remain anatomically focused, assessing only the degree of arterial stenosis caused by plaques. Positron emission tomography (PET) has allowed the metabolic processes within the plaque to be detected and quantified directly. The increasing armory of radiotracers has facilitated the imaging of distinct metabolic aspects of atherogenesis and plaque destabilization, including macrophagem e d i a t e d i n f l a m m a t o r y c h a n g e , h y p o x i a , a n d microcalcification. This imaging modality has not only furthered our understanding of the disease process in vivo with new insights into mechanisms but has also been utilized as a non-invasive endpoint measure in the development of novel treatments for atherosclerotic disease. This review provides grounding in the principles of PET imaging of atherosclerosis, the radioligands in use and in development, its research and clinical applications, and future developments for the field.
Atherosclerosis; Positron emission tomography; Coronary artery disease; Carotid stenosis
Published online: 23 April 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
Atherosclerosis is a leading cause of morbidity and mortality
in the Western world. It is a systemic inflammatory disease
that develops over decades, through initial vascular
endothelial dysfunction, circulating monocyte recruitment and
accumulation, maturation into a necrotic core, atheroma plaque
destabilization, and finally plaque rupture [
rupture, and subsequent atherothrombosis, is the primary etiology
for myocardial infarction, while large vessel (carotid)
atherosclerosis accounts for around one third of ischemic stroke
cases . As a reflection of the systemic nature of
atherosclerosis, concomitant disease in both coronary and carotid
arteries is estimated to occur in 28–58 % of asymptomatic
A challenge facing the clinical management of
atherosclerosis is differentiating between Bstable^ and Bvulnerable^
atherosclerotic plaques, those at risk of rupture and symptomatic
atherothrombosis. In clinical practice, the most commonly
used carotid imaging modalities are computed tomography
(CT) angiography and Doppler ultrasound. In coronary artery
disease, while invasive angiography remains the gold standard
anatomical imaging technique, non-invasive modalities (CT
angiography or perfusion) are increasingly being used for
individuals with stable symptoms and low to moderate risk
profiles. Within stroke care, medical versus surgical management
of carotid atherosclerosis is determined by the degree of
luminal stenosis on these investigations. However, this simple
anatomical criterion fails to consider other plaque
characteristics associated with risk of rupture. By combining samples
from the Oxford Plaque Study and the Athero-Express
Study, Howard et al. analyzed a pooled sample of 1640
symptomatic plaques. From this pooled data, they showed that
plaque thrombus, fibrous content, macrophage infiltration,
high microvessel density, and overall plaque instability were
each significantly associated with predicted stroke risk [
Non-stenotic carotid atheroma has been implicated as a
cause of previously classified Bcryptogenic^ stroke, with
non-stenotic plaques demonstrating high-risk morphological
features (hemorrhage, thrombus, or fibrous cap rupture)
having a higher association with ischemic stroke than those
without high-risk features [
]. Furthermore, intravascular
imaging of coronary artery atherosclerosis has demonstrated that a
significant atheroma burden with a high risk of subsequent
cardiac events may be present in the absence of luminal
stenosis due to outward artery remodeling [
findings of high-risk plaques in the presence of non-obstructive
lesions have been shown in humans with imaging of coronary
remodeling using CT [
These limitations of conventional anatomical imaging in
the assessment of atherosclerosis have led to increased interest
in non-invasive imaging methods to identify features of
plaque vulnerability and disease activity. Positron emission
tomography (PET) is one such imaging modality that can
detect and quantify the pathophysiological processes
associated with atherogenesis and subsequent plaque
destabilization. PET imaging was originally developed in the
midtwentieth century and is now used routinely in oncological
clinical care, though its use as a research tool to measure
pathophysiological processes in atherosclerosis is more
recent, beginning in 2002. These early atherosclerosis PET
imaging studies showed proof of principle for identification of
symptomatic carotid atheroma in human subjects, and
subsequent animal and human studies provided histological
validation. In the intervening 15 years, both animal and human
studies have been instrumental in the understanding of the disease
process through the development of new PET radiotracers.
Principles of PET/CT
The complex nature of atherogenesis provides a range of
pathophysiological pathways that may be exploited as targets for
imaging, many of which are amenable to PET. These targets
include inflammation, through hypoxia and apoptosis, to
microcalcification. PET utilizes positron-emitting radioligands
that accumulate at these different biological processes of
interest, their accrual within regions of interest (ROIs) resulting in a
localized concentration of emitted positrons that quickly
encounter electrons in neighboring tissues, leading to annihilation
reactions. Such reactions result in the emission of gamma
photons that can be detected by scintillation detectors in the
PET scanner. Regions of tracer uptake detected by PET must
be co-registered with CT imaging (PET/CT) or magnetic
resonance imaging (PET/MRI) to localize the pathophysiological
processes to an anatomical location.
A major advantage of PET is its very high sensitivity,
allowing picomolar tracer concentrations to be detected that
can be used to quantify the biological processes of interest.
The most appropriate method for measuring radiotracer activity
in vascular tissue remains a subject of debate and is discussed
in later sections. The conventional measurement methods are
the standardized uptake value (SUV) and tissue to background
ratio (TBR). SUV represents the ratio of radiotracer
concentration in the target tissue to the injected radiotracer activity
adjusted for weight. SUV may be further analyzed as SUVmax and
SUVmean. The SUVmax is calculated using the highest tissue
radiotracer concentration in the ROI, while SUVmean is
calculated using the mean tissue radiotracer concentration within the
whole ROI. In contrast, TBR was devised to correct for blood
uptake of radiotracer, the Bblood pooling^ effect. TBR is
calculated as the ratio of the SUVof the arterial wall to the SUV in
the mid-lumen of a large vein with no evident spill-over effect
from neighboring tissues [
Specific radioligands can be used in PET imaging to target the
metabolic processes involved in atherogenesis and plaque
disruption. Broadly, the main pathophysiological processes
associated with plaque vulnerability can be split into (i)
inflammation (with radioligands targeting macrophages, including
18Ffluorodeoxyglucose, somatostatin receptor ligands, and
translocator protein ligands), (ii) microcalcification
(18F-sodium fluoride), and (iii) hypoxia (18F-fluoromisonidazole).
While the technique is non-invasive, exposure to both the
radiotracer and CT scan involves ionizing radiation. A
250 MBq dose of 18F-fluorodeoxyglucose involves a radiation
exposure of 5 mSv, in addition to the 0.45 mSv from the CT
scan required for attenuation correction. Radiotracers
themselves have been shown to have an excellent safety profile,
with a review of 81,801 radiopharmaceutical doses showing
no recorded adverse reactions [
18F-fluorodeoxyglucose (FDG) is the mainstay radioligand in
PET imaging and consequently has been the most common
radioligand used in imaging studies of atherosclerosis.
Originally used for malignancy staging, incidental findings
of FDG accumulation in arterial territories during
wholebody scans heralded its utility for detecting and quantifying
inflammation within atheroma [
]. FDG, a radionucleotide
analog of glucose, accumulates intracellularly in proportion to
cellular demand for glucose. It is taken up into cells via
facilitated glucose transporter member (GLUT) 1 and 3, which are
upregulated during atherogenesis due to hypoxia within the
atheroma core and once inside the cytoplasm undergoes
phosphorylation by hexokinase to become 18F-FDG-6-phosphate.
18F-FDG-6-phosphate lacks a 2′ hydroxyl group and
consequently is unable to enter the Krebs cycle and undergo
glycolysis, subsequently diffusing slowly out of the cell. This
resulting accumulation is readily quantifiable and can be used
as a sensitive measure of metabolic activity, particularly given
its very high signal-to-noise ratios in tissues without high
metabolic activity (such as normal vessel wall and blood). The
high concentration of proinflammatory macrophages in the
vulnerable plaque provides such a tissue with a high metabolic
activity (Fig. 1).
FDG-PET’s ability to measure plaque inflammation
noninvasively in a symptomatic population was demonstrated in
early work by Rudd et al. where FDG uptake differentiated
between symptomatic and asymptomatic carotid atheroma in
human subjects [
], a finding that has been corroborated in
recent larger studies [19•]. This increased uptake of FDG
detected by PET/CT has been shown to correlate with
histological macrophage density in animal models [
excised atheroma following carotid endarterectomy [
FDG uptake has been shown to identify symptomatic
carotid plaques that were non-stenotic on high-resolution MRI,
supporting the concept that the severity of stenosis is not the
Fig. 1 FDG-PET/CT showing
high radiotracer uptake in the
right common carotid artery
sole determinant for symptomatic plaque rupture [
However, this small study contrasted with another small pilot
study that showed that although FDG uptake was higher in
symptomatic arteries, uptake also correlated with the degree of
]. In a large FDG-PET study by Tahara et al., only
29 % of asymptomatic individuals with carotid atherosclerosis
found on Doppler screening had FDG uptake within the
plaque, with no difference observed in the carotid
intimamedia thickness between inflamed and non-inflamed plaques
]. The observed association between increased FDG
uptake with high-risk morphological plaque features measured
by CT reinforces this finding and the shortcomings of solely
anatomical assessments of stenosis [
]. Multimodal imaging
studies using FDG-PET and MRI have allowed comparison of
tracer uptake with more accurate assessment of plaque
morphological features. Silvera et al. imaged individuals with
vascular risk factors and found FDG TBRmean to be higher for
lipid-rich plaques, which are often vulnerable to rupture, than
for collagen-rich or calcified plaques with a lower risk of
In addition to its relation with the index plaque rupture,
higher FDG uptake in carotid atheroma has been shown to
be associated with a higher risk of recurrent cerebrovascular
events, independent of the degree of luminal stenosis [
This is supported by an association of higher FDG uptake
and microemboli detected by transcranial Doppler [29•].
FDG-PET techniques have helped elucidate the systemic
nature of atherosclerosis (Fig. 2). FDG uptake correlates
Fig. 2 FDG-PET/CT showing
areas of focal radiotracer uptake
in the wall of the descending aorta
closely between neighboring arterial territories, suggesting a
global upregulation of inflammation rather than a localized
phenomenon [30••]. Joshi et al. demonstrated that FDG
uptake in the aorta reflected the clinical severity of coronary
syndromes, with a 20 % higher TBR in the aortas of those
with a recent myocardial infarction than those with stable
angina. Furthermore, within the group with myocardial
infarcts, the aortic FDG uptake was higher for those with an
ST elevation myocardial infarction than those with a non-ST
elevation myocardial infarction [
]. Similarly, carotid
SUVmean and TBRmean are significantly higher for cohorts
with acute coronary syndrome than for those with chronic
stable angina [
A possible mechanism for this relationship has been
demonstrated through the association between focal arterial
inflammation and systemic metabolic syndrome. Carotid
TBRmax is higher in both non-obese individuals with
metabolic syndrome and obese individuals without metabolic
syndrome compared to non-obese individuals without metabolic
]. Furthermore, both low-density lipoprotein and
total cholesterol have been shown to be independently
associated with FDG uptake [
]. These findings go some way
to explaining the association between higher Framingham risk
factor scores and higher TBR.
The interface between systemic inflammation driving
atheroma inflammation has been suggested by the association
between periodontal inflammation and inflammatory activity
within atheroma, both of which reduced in response to
atorvastatin and were strongly correlated [36, 37]. Serum
inflammatory markers have been found to be associated with an
increased risk of cardiovascular events, potentially
representing either a cause or result of an upregulated
inflammatory response [38–40]. Myeloperoxidase levels are
associated with a higher FDG TBR in carotid diseased segments,
independent of other conventional cardiovascular risk factors,
although no independent relationship was found for
highsensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6),
or matrix-metalloproteinase 9 (MMP-9) . However, other
studies have provided conflicting results, with an association
between higher TBR and higher levels of hsCRP [
comparison to blood biomarkers, FDG uptake can localize to
focal sites of high inflammatory activity. The focal plaque
inflammation on a background of a systemic inflammatory
reaction may account for the finding of neighboring regions
of FDG uptake.
Recent FDG-PET studies have continued to provide
insights into the interactions and contributions of different
aspects of the inflammatory process within atherosclerosis. In a
prospective FDG-PET study, regions of the aorta with high
SUV were more likely to develop calcification on subsequent
CT imaging, independent of cardiovascular risk factors .
Furthermore, in a substudy of the dal-PLAQUE study, Joshi et
al. found that FDG TBRs reduced over 6 months if carotid
calcification was absent, though there was no interval change
in tracer uptake in carotid arteries where calcification was
present . Consequently, the authors concluded that
calcium deposition is a propagating factor for ongoing arterial
The accumulation of cholesterol crystals within atheroma
has also been shown to promote plaque inflammation and
rupture in animal models, while crystal content found in
human carotid histology was found to be strongly associated
with plaque disruption, thrombus, and symptoms [45–47].
Though there is no PET radioligand for imaging cholesterol
crystals, instead relying on electron microscopy, their effect on
inflammation within the plaque may be measured. Patel et al.
showed that ezetimibe reduced the cholesterol crystal density
on electron microscopy in the aortas of atherosclerotic rabbits,
with a corresponding decrease in inflammation as quantified
by FDG uptake (SUVmax), CRP, and MMP-9 levels .
FDG-PET has a number of advantages, but also limitations,
compared to other imaging modalities. It is highly
reproducible with high intra-observer and inter-observer agreement
. PET/CT using FDG has a high sensitivity for detecting
inflammation in plaques, but its utility to detect inflammation
may be hindered when the ROI is in close proximity to other
tissues with tracer uptake due to high resting metabolic rates
(such as neurons and myocardial tissue) and may be further
compounded by the low spatial resolution of PET
(approximately 3 mm). Solutions for both of these weaknesses are
currently being developed with the advent of more
cellspecific ligands and PET/MRI. Dynamic contrast enhanced
(DCE) MRI has been shown to have superior spatial
resolution than PET/CT, and contrast enhancement has been
particularly effective in the assessment of fibrous cap thickness and
lipid core volume, where the former enhances while the latter
fails to enhance . Multicontrast-weighted MRI has been
used in surveillance of asymptomatic plaques and
demonstrated larger lipid cores, thicker MWT, thin/ruptured fibrous caps,
and intraplaque hemorrhage to each have significantly
increased hazard ratios for subsequent symptomatic events
. However, while MRI offers an effective method for
imaging morphological features associated with plaque
vulnerability, it remains dependent on accurate coil placement as well
as the reproducibility of technical sequences and image
generation. These considerations, along with a desire to image
directly the biological activity in the plaque, has led to DCE
MRI and PET/CT providing complementary imaging of the
plaque, though the advent of PET/MRI may enable a fusion of
these techniques and is discussed further below.
Translocator Protein Ligands
While FDG-PET has become a mainstay of metabolic
imaging in atherosclerosis in a relatively short time, its lack of
specificity means that proximity of the artery of interest to
other highly metabolically active structures, such as the
myocardium, limits its utility. Alternative radiotracers
targeting macrophage-driven inflammation via their
expression of translocator protein (TSPO) have been investigated
with the goal of providing higher specificity than that offered
by FDG. 11C-PK11195
TSPO expressed on macrophages and microglia and has been
shown to detect these inflammatory cells in atheroma and
around the stroke penumbra, respectively. Specific to
atherosclerosis, 11C-PK11195 uptake was found to be higher in
inflamed than non-inflamed plaques in a mouse model, though
its utility as a tracer was limited due to a non-significant
difference between plaque and healthy vessel wall . This
likely reflects the ubiquitous nature of TSPO expression by
a range of cells and organs, despite the upregulation in
activated plaque macrophages, but may also reflect the limitations
of using mouse models of plaque, especially vulnerable
plaques, compared to humans. Subsequent studies in human
subjects have shown more promise, with 11C-PK11195 TBR
found to be higher in symptomatic versus asymptomatic
carotid arteries (TBR 1.06 ± 0.2 and 0.86 ± 0.11, respectively,
p = 0.001) despite a lower grade of stenosis in asymptomatic
arteries . 11C-PK11195 uptake has been found to
colocalize with activated macrophages using autoradiography
and CD68 staining of ex vivo carotid histology [54, 55].
However, the ubiquitous uptake in healthy vessel wall may
limit the utility of 11C-PK11195-PET in clinical
Newer TSPO ligands are in development, labeled with 18F
rather than 11C. There has been increasing interest in
2,3,4,9tetrahydro-1H-carbamazole-4-carboxamide) to replace
PK11195 as the TPSO ligand of choice to image
neuroinflammation and potentially atherosclerotic plaque inflammation.
Animal models have shown 18F-GE-180 to have a
significantly higher binding potential than that of PK-11195, improved
signal-to-noise ratio, and lower non-specific binding in and
around infarcted cerebral tissue [56, 57]. The use of 18F in
contrast to 11C has other benefits including a longer half-life.
However, the utility of such second-generation TSPO
radioligands in PET imaging may be limited owing to variable
receptor binding affinity due to genetic polymorphisms
[58–60]. Further work is required to assess the utility of
18FGE-180 and other second-generation TSPO ligands for
imaging both plaque inflammation and neuroinflammation.
68Ga-DOTATATE and 64Cu-DOTATATE
Another clinically available PET radioligand under
investigation for use in atherosclerosis imaging is DOTATATE ([1,4,7,
acid]-dPhe1,Tyr3-octrotate). DOTATATE binds to somatostatin
receptor subtype-2 (SST2), which appears to be upregulated
on the surface of activated macrophages [61, 62]. The low
physiological expression of SST2 by the myocardium
suggests that this tracer may be advantageous for targeting disease
in the coronary arteries.
Vascular 68Ga-DOTATATE uptake has been imaged in
asymptomatic individuals with cardiovascular risk factors and
coronary calcification [63–65] and in aortic atherosclerotic
plaques in a mouse model . In a retrospective series of
DOTATATE-PET imaging performed in oncological practice,
Rominger et al. found 68Ga-DOTATATE-PET to have an
excellent intra-reader and inter-reader reproducibility for TBR
readings in the left anterior descending coronary artery (intra-class
correlation coefficients of 0.97 and 0.94, respectively) .
64Cu-DOTATATE has also been investigated for use in
carotid imaging. The longer half-life of 64Cu compared to
68Ga (12.7 h versus 68 min) and shorter maximum positron
range provide several theoretical advantages, although this
must be balanced against the wider availability of the
generator-produced 68Ga compared to the
cyclotronproduced 64Cu. In a proof-of-principle study using PET/
MRI, Pedersen et al. demonstrated carotid 64Cu-DOTATATE
uptake correlated with gene expression of macrophage
markers CD68 and CD163 using univariable analysis, though
only correlation with CD163 expression remained significant
on multivariable analysis . DOTATATE’s propensity
toward CD163+ macrophages, as well as findings of
atheromatous regions with DOTATATE but no FDG uptake, suggests
that DOTATATE is able to identify a different component of
the inflammatory process compared to conventional
FDGPET [65, 67]. Increased 64Cu-DOTATATE signal has also
been reported in individuals with cardiovascular risk factors
in a retrospective study .
Although DOTATATE-PET has shown early promise as a
potential candidate radiotracer for imaging inflammation in
atherosclerosis, this newer technique has not yet been tested
in large human studies in individuals with symptomatic
disease. Further prospective clinical studies and histological
validation are needed.
Inflammation is not the sole metabolic process contributing to
plaque vulnerability. Inflammation within the atheroma can
promote microcalcification, the formation of deposits of
calcium smaller than 50 μm, through cytokine-mediated
promotion of osteoblast-like cells derived from vascular smooth
muscle cells [
]. Plaque macrophage burden showed a
strong association with osteoblastic activity in the aortas of
hyperlipidemic mice, and both macrophage burden and
osteogenic activity increased with plaque progression .
Microcalcification may predispose to plaque rupture either
through mechanical disruption to the fibrous cap and/or
provoking ongoing inflammation around the deposit.
18F-sodium fluoride (NaF) used in PET imaging is able to
identify areas of microcalcification in vivo because the
radiolabeled fluoride is taken up at sites of mineralization,
where it replaces the hydroxyl group of hydroxylapatite [
(Fig. 3). Work by Irkle et al. validated clinical NaF-PET using
NaF against electron microscopy, autoradiography, and
microPET for detecting microcalcification in symptomatic
carotid endarterectomy histological specimens. Fluoride was
shown to co-localize closely and preferentially bind to
pathological mineralization, and the increased surface area of
microcalcification relative to macrocalcification resulted in
increased tracer uptake [74••].
The feasibility of NaF-PET to identify microcalcification in
atherosclerotic plaques was demonstrated by Derlin et al. in a
cohort of patients undergoing full-body NaF-PET/CT for
oncological staging of bone metastases. This study showed that NaF
uptake may occur at sites of macrocalcification, but distinct areas
of NaF uptake and macrocalcification occurring in isolation
demonstrated that NaF uptake reflects the active mineralization
process in microcalcification rather than simply the burden of
]. Further lack of co-localization between
regional macrocalcification and regional NaF uptake has been
found in other asymptomatic cohorts, with an inverse
relationship between NaF uptake and plaque calcium score [
Morbelli et al. demonstrate that the presence of cardiovascular
risk factors correlate with NaF uptake but not arterial
macrocalcification, though the study’s measurement of uptake
across the whole vessel may miss focal concomitant areas of
macrocalcification and NaF uptake . Further studies have
found that carotid NaF uptake correlated with the presence of
cardiovascular risk factors in an asymptomatic population [
Derlin et al. performed a dual-tracer PET/CT study using
FDGPET and NaF-PET in a further asymptomatic oncological patient
cohort and found that of 215 arterial lesions identified by either
tracer, only in 14 (6.5 %) was there concomitant FDG and NaF
uptake, implying that macrophage-driven inflammation and
microcalcification are two related but distinct processes [
A prospective study has shown that NaF TBRmax is higher in
individuals with coronary artery disease, stable angina, or
previous cardiovascular events [
]. Increased tracer uptake has been
shown to be associated with symptomatic coronary plaques, with
the increased uptake seen in morphologically high risk but
unruptured plaques suggesting that uptake reflects the
microcalcification process rather than increased surface area
following plaque rupture [81••]. In contrast, no significant
difference in NaF uptake between symptomatic and asymptomatic
carotids was found in a cohort of stroke patients, though the
number of patients was small with long bolus to scan times [
The inter-rater repeatability of NaF-PET/CT is high, with an
intra-class coefficient of 0.99 found in one study [
improvements in the quantification of microcalcification in
coronary atherosclerosis is likely following developments in
motion correction resulting in an improved signal-to-noise ratio,
Fig. 3 Lower limb 18F-NaF
imaging: non-contrast CT (top
left) with a rim of calcification of
the vessel, 18F-NaF PET (top
right), and fused 18F-NaF PET/
CT (bottom left) of the superficial
femoral artery (arrow) at the level
of the adductor canal,
demonstrating significant vessel
uptake in this symptomatic
patient. In addition, there is
prominent uptake seen in the
vessel at the same level on the
coronal image (bottom right)
reducing signal Bspill-over^ from motion causing the
radiotracer signal (detected over minutes) to fall outside the ROI
determined from anatomical scans (taken over seconds) [
triazol-1-yl)propan-1-ol), has been shown to have specific
uptake in regions of plaque with a strong correlation between
TBRmax and carotid arterial wall dimensions on 3.0-T MRI [
Atherosclerosis is often associated with hypoxia, presumably
due to an increasing oxygen demand from foam cells. This
likely results from reduced diffusion efficiency from lumen to
wall as plaque thickness increases [
potentiates the inflammatory response via hypoxia-inducible
factor1α (HIF-1α) expressed by macrophages in the core, a
response that may be further upregulated by the presence of
oxidized low-density lipoprotein [
]. Whereas structural
imaging techniques can assess the size of the necrotic core of
the plaque, PET imaging using 18F-fluoromisonidazole
(FMISO) can measure the effects of hypoxia within the core
directly. In a hypoxic environment, the FMISO is reduced and,
in the absence of reoxidation, remains bound intracellularly.
Mateo et al. demonstrated that in a hyperlipidemic rabbit
model, FMISO uptake was significantly higher in regions of
atheroma than in normal tissue. Furthermore,
immunohistochemistry showed the hypoxia to be deep in the core rather than at
the luminal boundary [
]. In an early clinical study, FMISO
TBR was found to be higher in symptomatic than
asymptomatic carotid atherosclerosis, with FMISO uptake correlating
with FDG uptake, suggesting that hypoxia is a contributing
factor in FDG uptake [
Recently, another radioligand targeting plaque hypoxia,
There are a number of methodological and technical
considerations in PET/CT assessment of the plaque. At a single study
level, these primarily include partial volume correction and
methods of tracer uptake quantification. In contrast, the use of
different study protocols within the field also has implications for
reproducibility and the ability to pool results in larger
Partial Volume Correction
Measurement of tracer uptake within the atheroma is
dependent upon the size of the atheroma and the resolution of the
scanner. The partial-volume effect occurs when limited
resolution results in difficulty differentiating the tracer activity of
the ROI from the tracer activity of the surrounding tissues.
This may lead to Bspill-out,^ where the tracer signal from
the atheroma falls outside of the ROI, and Bspill-in^ where
tracer signal from adjacent tissue falls within the ROI. The
combination of these two effects results in partial volume error
(PVE). Small atheromatous lesions falling below the spatial
resolution of the scanner are particularly at risk of PVE. It is
estimated that the dimensions of a homogenous ROI need to
be two to three times the spatial resolution of the scanner in
order to minimize PVE [
]. Reduction of PVE through
partial volume correction (PVC) can be performed using a
geometric transfer matrix (GTM), whereby co-registration with a
higher resolution modality allows restriction of the tracer
signal to a corresponding voxel-based volume of interest that can
then undergo further voxel-based adjustment for PVE using
an algorithm proposed by Rousset el al. [
]. This method has
been applied to atheroma imaging (using co-registration with
MRI) and was found to improve quantification of tracer
activity and to be highly reproducible [
SUV Versus TBR
Studies conducted to date have varied in their use of SUVor TBR,
and the most appropriate quantification method remains a subject
of debate [
]. In plaque simulations based on real patient data,
marked bias was found in both measured SUVmax and SUVmean
compared to the modeled values, largely due to the spatial
resolution of the reconstructed image typically being more than three
times the thickness of the atherosclerotic plaque, resulting in a
reduced ability to correct for PVE. Bias was more marked when
fewer iterations were used during image reconstruction [
In a study of 32 patients undergoing endarterectomy, Niccoli
et al. compared the ability of SUVmax, SUVmean, TBRmax, and
TBRmean to differentiate in vivo plaques classified as either
inflamed or non-inflamed following histological examination ex
vivo. Within the symptomatic arteries, the authors found that the
differences for SUVmax and SUVmean between inflamed and
non-inflamed plaques were non-significant, while both TBRmax
and TBRmean were able to differentiate between plaques found to
be inflamed or non-inflamed on histology [
TBR has limitations, and its application is not without its
criticisms. Blood-pool SUV has been shown to decrease with
increasing injection to scan intervals (mean SUV within the
jugular vein was 1.04 ± 0.16 at 1 h, 0.79 ± 0.03 at 2 h, 0.66
± 0.04 at 3 h). Consequently, plaque TBR values differed
significantly between cohorts scanned at 2 and 3 h. In contrast, tissue
SUVmax did not differ between these time points [
Furthermore, impaired renal function will also contribute to
increased blood-pool activity. Blood-pool SUV has been found to
be inversely proportional to the estimated glomerular filtration
rate, resulting in a lower TBR with lower renal clearance [
There has been an overall shift toward TBR in arterial PET
imaging, but the possible confounders described above must
be considered when comparing results both within the same
study and against other studies. Standardization of scan
methodologies and patient cohorts will help address this.
Increasingly, specific radioligands have resulted in improved
signal-to-background ratios and reproducibility, with high
intra-rater and inter-rater reproducibility reported for NaF
and 68Ga-DOTATATE [
]. However, a major
consideration within the field of vascular PET imaging is the wider
reproducibility of individual studies. Typically, most vascular
PET studies of symptomatic patients are small, with fewer
than 50 participants, due to a combination of sufficient
statistical power with small participant numbers balanced against
radiation exposure and high economic costs. While the
multitude of FDG studies would seem prime for meta-analysis, the
heterogeneous patient populations and variations in
methodology pose barriers to such analyses. Variations in tracer
doses, interval between symptoms and imaging, blood
glucose thresholds, and measurement techniques (SUV versus
TBR) are a few of the differences in studies that make direct
comparison difficult. The effect of the symptom to scan
interval on the potential variability of the PET signal is difficult to
quantify as radiation exposure is a barrier to longitudinal
studies and should therefore be analyzed in any multivariate
analysis. Consequently, there is a move toward establishing a
recognized common standard for arterial PET imaging. A recent
position paper from the European Association of Nuclear
Medicine has recommended such common standards for
FDG-PET, particularly with regards to injected dose,
circulation uptake time, prescan fasting glucose limits, and suggested
quantification using TBR in most cases [
]. Adopting a
unified approach to scanning protocols and quantification will
allow the high inter-rater reproducibility to be exploited,
existing data to be pooled into larger meta-analyses, and
standardization of multicenter PET imaging studies.
PET/CT Applications in Atherosclerosis Drug Trials
As well as its utility for understanding the pathophysiology of
atherosclerosis, PET/CT has an important application for
measuring the effects of drug treatment. FDG-PET has also
offered key insights into mechanisms of atheroma stabilization
with statins, in particular their observed anti-inflammatory
effects upon the atheroma in addition to their effect on lipid
The capacity to measure atherosclerotic metabolic
processes non-invasively in vivo has been shown to provide a useful
endpoint for drug discovery and efficacy trials. The
dalPLAQUE phase 2b randomized clinical trial of dalcetrapib
(a modulator of cholesteryl ester transfer protein that raises
high-density lipoprotein cholesterol) used FDG uptake as its
primary endpoint and demonstrated that there was no safety
concerns over the 6 months while on dalcetrapib. In this study,
dalcetrapib failed to reduce carotid FDG uptake when
compared to placebo, which was consistent with the later
randomized placebo-controlled clinical outcome study [
FDG-PET endpoints have also been used by Emami et al.
who used it to compare the therapeutic effects of
BMS582949 (a p38 mitogen-activated protein kinase inhibitor)
against placebo, but again, no significant difference was seen
between these two cohorts [
]. This study did reinforce the
finding that statin treatment leads to a reduction in FDG
uptake in the control group, and this may contribute to the lack of
significance between cohorts. These studies serve as an
important proof of principle for the use of PET endpoints in
randomized clinical trials.
Recent advances have led to the feasibility of MRI for
anatomical co-registration with PET. PET/MRI has a number of
potential advantages over PET/CT. MRI, using either contrast
enhancement or black-blood imaging, has proven to be an
effective non-invasive imaging modality for assessing and
quantifying plaque morphological features. The
complementary nature of MRI and PET for assessing plaque morphology
and metabolism, respectively, is advantageous in the
identification of vulnerable plaques [
27, 105, 106
currently, this requires two different scans with consequent
difficulties for co-registration. Recent small studies on hybrid PET/
MRI scanners have shown promising proof-of-principle data
for combined morphological and metabolic imaging of
atherosclerosis. In an asymptomatic cohort, Ripa et al. found a
moderate to good correlation for PET/CT and PET/MRI FDG
SUVmax (r = 0.6) and SUVmean (r = 0.8) on carotid
vessel-byvessel comparison, though there was noted a small but
significant under-reading for PET/MRI of less than −0.2 for both
SUVmax and SUVmean [
]. Hyafil et al. performed
FDGPET/MRI in a cohort of 18 cryptogenic strokes for individuals
with Bnon-stenosing^ carotid disease (i.e., stenosis measured
as ≤50 %) and found that there was a significantly higher
proportion of plaques with the highest morphological features
of vulnerability (AHA lesion type 6, so-called complicated
plaques) in the ipsilateral carotid compared to the side
contralateral to the infarct. The FDG TBRmean of both the ipsilateral
and contralateral carotid arteries of individuals found to have
AHA type 6 lesions was higher than the TBRmean of
individuals without complicated carotid disease [
larger studies are required to evaluate the utility of PET/
MRI, in particular regarding considerations such as
attenuation correction and the implications for PVE.
The evolution of atherosclerosis imaging from anatomical to
metabolic imaging has provided novel insights into the
pathophysiology underlying atherogenesis and plaque
vulnerability. Broad adoption within routine clinical care is currently
limited by availability, cost, and radiation exposure.
However, as a research tool, it has facilitated the introduction
of metabolic endpoints in studies of new treatments for
atherosclerosis, as well as a means to measure the therapeutic
effects of existing treatments. Translation of PET/CT
techniques such as these to the clinical setting will require phase
3 trials where treatment decisions are made on the basis of
metabolic imaging data rather than conventional structural
imaging. The potential for newer, more specific radioligands
and the increasing availability of PET/MRI is likely to
advance our understanding of atherosclerosis and help the
development of novel therapeutics to combat this important
Acknowledgments NRE is supported by a research training fellowship
from The Dunhill Medical Trust [grant number RTF44/0114]. JMT is
supported by a Wellcome Trust research training fellowship (104492/Z/
14/Z). MMC is part-supported by the Royal College of Surgeons of
England Fellowship Program. JHFR is part-supported by the HEFCE,
the NIHR Cambridge Biomedical Research Centre, the British Heart
Foundation, and the Wellcome Trust.
Compliance with Ethical Standards
Conflict of Interest Nicholas R. Evans declares grant support from The
Dunhill Medical Trust (Research Training Fellowship).
Jason M. Tarkin declares grant support from the Wellcome Trust
(Research Training Fellowship).
Mohammed M. Chowdhury declares grant support from the Royal
College of Surgeons (Freemasons’ Fellowship).
Elizabeth A. Warburton declares grant support from the British Heart
Foundation and the National Institute for Health Research.
James H. F. Rudd declares grant support from the Higher Education
Funding Council for England, Cambridge Biomedical Research Centre,
British Heart Foundation, and the Wellcome Trust.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Open Access This article is distributed under the terms of the Creative
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