Atlas of nuclear cardiology

425V. Dilsizian, J. Narula (eds.), Atlas of Nuclear Cardiology: Fourth Edition,
DOI 10.1007/978-1-4614-5551-6_12, © Springer Science+Business Media, LLC 2013
12Molecular Imaging
of Atherosclerosis
Ahmed Tawakol, Jagat Narula,
and Farouc A. Jaffer
Significant advances have been made toward the management of coronary disease,
but it is not yet possible to clinically identify patients likely to develop an acute coronary
event. Although the presence of risk factors and circulating biomarkers enables the
identification of vulnerable patients, it is necessary to prospectively recognize the rup-
ture-prone atherosclerotic plaque to prevent occurrences of acute events. For such a
strategy to be successful, emphasis needs to be placed on the structural and molecular
characteristics underlying coronary plaques of interest. The majority of acute coronary
syndromes (ACS) arise from disrupted plaques that may not always be significantly
obstructive. Histopathologic data reveal that “vulnerable plaques” are usually volumi-
nous with significant expansive remodeling, contain bulky necrotic cores with neovas-
cularization and intraplaque hemorrhage, and are covered by attenuated and
inflamed fibrous caps. They are usually not heavily calcified. It has been proposed that
the outwardly remodeled vascular segments and low-attenuation plaques can be
detected by multislice CT with reasonable diagnostic accuracy. On the other hand,
plaque volumes, lipid accumulation, and intraplaque hemorrhage have been identified
by MRI in large and less mobile noncoronary vasculature. The assessment of the thick-
ness of the fibrous cap has required invasive instrumentation such as optical coherence
tomography (OCT). Plaque inflammation, apoptosis, and angiogenesis are amenable
to molecular imaging [1–4].
The role of inflammation in driving and defining plaque vulnerability is well established
[5]. Recent trials have demonstrated that the circulating biomarkers of inflammation
help predict the likelihood of acute vascular events even when cholesterol levels are
not very high. While biomarkers allow an assessment of the inflammatory state in gen-
eral, it will be attractive to recognize inflamed plaques locally in clinically relevant vas-
cular beds (coronary and carotid arteries), to both refine risk prediction and guide novel
therapeutic strategies targeted for local intervention and primary prevention of acute
vascular events.

426 Atlas of Nuclear Cardiology
Pathologic Substrates for Imaging Vulnerable Plaques
Plaque rupture is responsible for up to 75 % of acute coronary events [3, 4]. The rupture of the fibrous cap exposes
a thrombogenic core to the luminal blood and leads to acute thrombosis. Disrupted plaques have distinct patho-
logic characteristics; they are generally large both cross-sectionally and longitudinally. These voluminous plaques
may not necessarily impose significant luminal obstruction because the arterial wall at the lesion site is outwardly
(positive or expansively) remodeled. These plaques contain large necrotic cores. The disrupted fibrous caps are
thin and infiltrated by macrophages.
a b
FIGURE 12-1. Pathologic characteristics of a stable and a rup-
tured plaque. The stable plaque is rich in collagen and smooth
muscle with minimal lipid accumulation (a). On the other hand,
ruptured plaque is formed predominantly by a large necrotic
core (asterisk) and covered by a thin fibrous cap (b). The site of
plaque rupture (arrow) exposes the necrotic core to luminal
blood and allows thrombotic occlusion of the vessel. The
pathologic examination of culprit plaques from the victims of
ACS reveals that these plaques are usually significantly volumi-
nous. Up to 95 % of the disrupted plaques demonstrate greater
than 50 % cross-sectional vascular area involvement, and
about 50 % of the ruptured plaques occupy more than 75 % of
the cross-sectional area of the vessel (Adapted from Shapiro
et al. [4]).
ba
FIGURE 12-2. (a) Disrupted plaques usually demonstrate large
necrotic cores (NC). In the culprit plaques, the NC usually
occupy greater than 25 % of the plaque area and show more
than 120° circumferential involvement of the vessel in at least
75 % of instances. The NC extend 2–22 mm in longitudinal
dimension (median, 9 mm). The larger the plaque area and
the larger the NC size, the higher the likelihood of plaque insta-
bility [3, 4]. (b) It is reasonable to presume that before the
acute event, plaques vulnerable to rupture harbor the same
histopathologic signatures, except that the thin fibrous cap is
still intact. Up to 40 % of the vulnerable plaques occupy more
than 75 % of the cross-sectional vascular area and an addi-
tional 50 % encroach on 50–75 % of the vascular area. In the
latter instances, the large plaque volume is accommodated
by positive remodeling of the vessel (Adapted from Shapiro
et al. [4]).

Molecular Imaging of Atherosclerosis 427
a b
c
d e
FIGURE 12-3. (a–e) Evolution of necrotic core (NC) in the plaque.
The ongoing death of lipid-laden macrophages contributes to
the formation of the NC in atherosclerotic plaques. Worsening
hypoxia in the enlarging plaque perpetuates macrophage
death, enlarges the NC, and promotes neovascularization (b)
[6]. These nascent vessels are inherently leaky and allow
extravasation of red blood cells (RBC) into the plaque (c). It is
well appreciated that the cholesterol content of erythrocyte
membranes exceeds that of most other cells in the body and
likely contributes to the cholesterol pool of the growing NC.
Intraplaque hemorrhage (c) due to the rupture of these imma-
ture vessels further leads to the accumulation of a large num-
ber of RBC and, hence, cholesterol. The plaque hemorrhages
are common in the coronary arteries in patients dying from
plaque rupture. The extent of iron deposits (e) in the plaque (Fe)
and that of glycophorin A (d) (GpA, a protein exclusively asso-
ciated with RBC membrane) staining is directly proportional to
the size of the NC [7, 8]. Plaque neovascularization is accompa-
nied by proliferation of vasa vasorum (a) [8, 9]. Disrupted
plaques have a fourfold higher vasa vasorum density com-
pared with stable plaques with severe luminal narrowing.
Microvessels that perforate from the adventitial layer to the
medial layer are well formed with the smooth muscle cell (SMC)
envelope, unlike those that extend to the neointima, which
appear immature and leaky. Abundant T-helper cells found at
the medial wall perforation site likely inhibit SMC proliferation
through interferon. The density of vasa vasorum, measured by
micro-CT, increases markedly during hypercholesterolemia and
resolves with statin treatment. The increase in vasa vasorum is
associated with vascular endothelial growth factor expression
in the neointima and neoangiogenesis. Interestingly, erythro-
cyte membrane-derived cholesterol is elevated in patients pre-
senting with ACS and is sensitive to statin therapy (a – Adapted
from Kwon et al. [6]; b – Adapted from Kolodgie et al. [9]).

25
a b
20
15
10
5
All
CL-related
NCL-related
Indeterminate
0 1 2 3
Time, years
0
MACE,%
13.2
7.9
6.4
0.9
18.1
11.4
9.4
1.9
20.4
12.9
11.6
2.7
c
5
0
15
10
20
Median3.4-yearsMACErateperlesion,%
Present
Absent
TCFA TCFA + MLA
≤4.0 mm
2
TCFA + PB
≥70 %
TCFA + PB
≥70 % +
MLA ≤ 4 mm
2
4.4
1.2
9.2
1.5
15.3
17.2
1.5 1.8
5
0
15
10
20
Present
Absent
PIT PIT + MLA
≤4.0 mm
2
PIT + PB
≥70 %
PIT + PB
≥70 % +
MLA ≤ 4 mm2
0.6
2.7 2.31.9 2.6
5.9
1.9 1.9
FIGURE 12-4. Intravascular ultrasound (IVUS) offers accurate mea-
surements of the minimal lumen area (MLA), plaque burden
(PB), and type of remodeling, and radiofrequency IVUS even
allows reasonable determination of fibrous (green) and necrotic
core-rich (red) composition of the plaque. (a) Demonstrates
predominantly fibrous pathologic intimal thickening (PIT, right)
and predominantly lipid-rich (left) plaques. It has been pro-
posed that a shallow necrotic core abutting the lumen may
represent a thin cap fibroatheroma (TCFA). (b) In a landmark
prospective study, almost 700 patients with ACS underwent
three-vessel coronary angiography and IVUS imaging after per-
cutaneous coronary intervention. Subsequent major adverse
cardiovascular events (MACE; death from cardiac causes, car-
diac arrest, myocardial infarction, or rehospitalization due to
unstable or progressive angina) were adjudicated to be related
to either originally treated (culprit) lesions or untreated
(nonculprit) lesions, over a median follow-up period of more
than 3 years. The cumulative rate of major adverse cardiovas-
cular events was 20 %: 13 % related to culprit lesions (CLs) and
12 % to nonculprit lesions (NCLs). Although most NCLs responsi-
ble for follow-up events were angiographically mild at baseline
(luminal diameter stenosis, 32±21 %), they progressed to 65±16 %
diameter stenosis at the time of the follow-up event (P<0.001).
(c) Event rates associated with almost 600 NCLs characterized
as TCFA and 2,000 PIT are shown according to MLA and PB, as
detected on gray-scale and radiofrequency IVUS. (Prevalence
data are for one or more such lesions per patient; lesions in
patients with indeterminate events are excluded.) The recurrent
events were associated with a PB greater than 70 % (hazard
ratio [HR]=5; 95 % CI, 2.5–10; P<0.001), MLA less than 4.0 mm2
(HR=3; 95 % CI, 2–6; P=0.001), or TCFA (HR=3; 95 % CI, 2–6;
P<0.001) [10] (Courtesy of Gregg Stone, MD, New York).
Imaging of Morphologic Characteristics
Imaging of morphologic characteristics of atherosclerotic plaques. Intravascular ultrasound and CT angiography
offer an excellent assessment of the magnitude of the plaque, the necrotic core size, and the extent of positive
remodeling; thin fibrous caps can be quantitatively characterized by intravascular high-resolution OCT.

Stable Culprit
a b
FIGURE 12-5. Multislice CTA of stable (a) and culprit (b) coronary
lesions with invasive coronary angiogram. The culprit lesion is
outwardly remodeled (yellow arrows in inset) compared with
the proximal normal vessel and contains low-attenuation (likely
soft) plaque (red arrows) [11]. The stable lesion is not remod-
eled and shows intermediate attenuation (likely fibrous) plaque
(green arrow). The culprit lesions have also been demonstrated
to be more frequently associated with spotty calcific deposits
but not large calcific plates. If plaques with similar CTA charac-
teristics are identified incidentally, up to one fourth of them
may develop ACS during a 2-year follow-up period [12].
Plaques with stable characteristics are associated with a less
than 0.5 % likelihood of an acute cardiac event. The fibrous
caps are significantly attenuated in the vulnerable plaques
and are disrupted at the weakest site in an acute coronary
event. Based on a large set of disrupted plaques postmortem,
it was proposed that fibrous cap thickness of less than 65 mm
predicts vulnerability to plaque rupture. The fibrous cap thick-
ness can be accurately measured by OCT [13] (Adapted from
Motoyama et al. [11]).

FIGURE 12-7. Ultrasound microbubble studies have identiﬁed
increased vasa vasorum and plaque vascularity in patients
with carotid atherosclerosis [16]. A longitudinal image of a
carotid artery has become well visualized after contrast admin-
istration and distinguishes the intimal-medial thickness of the
anterior and posterior walls. Note the striking pattern of vasa
vasorum neovascularization leading to the core of the
atherosclerotic plaque (arrow). This patient had diabetes and
was not receiving statin therapy. Subsequent to the recording
of these images, the patient underwent a carotid endarterec-
tomy for symptomatic cerebral vascular disease; the endart-
erectomy specimen revealed a plethora of microvasculature
within the matrix of the plaque and residual deposits of hemo-
siderin resulting from prior hemorrhage (inset).
Hemorrhage
with cholesterol
crystals
Recent
hemorrhage
TOF T1W
PDW T2W
FIGURE 12-6. Noninvasive imaging of intraplaque hemorrhage.
Magnetic resonance T1-weighted imaging of carotid arteries
has demonstrated high diagnostic accuracy for histologically
veriﬁed plaque hemorrhage in resected carotid endarterec-
tomy specimens [14]. It has been demonstrated that the
plaques with intraplaque hemorrhage almost invariably
demonstrate an increase in plaque volume on follow-up, even
if treated with high doses of statins. In addition, patients with no
plaque hemorrhage frequently decrease their plaque volume
after statin treatment. On the other hand, the T2* values are
lower in carotid lesions with intraplaque hemorrhage [15].

b
a
FIGURE 12-8. Optical coherence tomography for the measure-
ment of fibrous cap thickness. OCT has a high resolution and is
the only current modality that allows assessment of fibrous cap
thickness. The widely accepted threshold of less than 65 mm for
thin cap fibroatheroma was derived from postmortem studies
of ruptured plaques. In an OCT study of more than 100 patients
with ACS and more than 150 patients with stable angina
before percutaneous coronary intervention, ruptured (a) and
nonruptured (b) lipid-rich plaques were identified and the thin-
nest and most representative fibrous cap thickness was deter-
mined. From the ruptured plaques, the median thinnest cap
thickness was 54 mm (50–60 mm). For nonruptured plaques, the
median thinnest cap thickness was 80 mm (67–104 mm). The
best cutoffs for predicting rupture were less than 67 mm (odds
ratio, 16; CI, 8–34; P<0.001) for the thinnest cap thickness
(Adapted from Yonetsu et al. [17]).

Inflammation, Plaque Vulnerability, and Molecular Imaging
a
d
b
c
Macrophages,%
6
4
2
0
<65 <200
P = 0.03
<300
Fibrous cap thickness
>300 μ
NC
Th
Th
MAC
FIGURE 12-9. Fibrous cap inflammation in ruptured plaques. The
thin fibrous caps of the ruptured or vulnerable plaques are
markedly inflamed with monocyte-macrophage infiltration. In
a histologic section of coronary vessel obtained from a sudden
death victim, a huge concentric plaque and cholesterol crys-
tal-rich necrotic core (NC) are seen. The thin fibrous cap is dis-
rupted and thrombus (Th) occludes the lumen. The area
enclosed by the black square in (a) is magnified in (b); the yel-
low boxed area is further magnified and stained for mac-
rophages (MAC) (c) [4]. The disrupted site is significantly
inflamed. Analysis of fibrous caps demonstrates that
macrophages are the most dominant cellular population in
ruptured and vulnerable plaques, whereas SMCs are dominant
in stable atherosclerotic lesions. Higher numbers of mac-
rophages are associated with thinner fibrous caps (d).
Macrophages presently are best targeted by employing
18
F-fluorodeoxyglucose (FDG) for PET molecular imaging.
Although multiple targeting strategies have been employed in
experimental disease models and clinically in peripheral vas-
culature, FDG-PET/CT imaging of atherosclerotic inflammation
has been studied most extensively.

FIGURE 12-10. (a) Fluorodeoxyglucose accumulation is a mea-
sure of the tissues’ glycolytic rate. FDG, which is structurally simi-
lar to glucose, enters cells through GLUT transporter proteins.
Within cells, FDG is phosphorylated by hexokinase to generate
FDG-6-phosphate. However, while glucose-6-phosphate can
participate in further glycolysis, FDG-6-phosphate cannot.
Therefore, it is metabolically trapped and accumulates within
the tissue in relation to the rate of glycolysis. (b) Macrophage
activation substantially increases the rate of glycolysis. At base-
line, prior to stimulation, macrophages produce adenosine-5¢-
triphosphate (ATP) at a relatively modest rate. Further, ATP
synthesis in the basal state is relatively evenly distributed
between glycolytic and mitochondrial ATP syntheses. After
stimulation with interferon gamma and lipopolysaccharide
(LPS), the total ATP synthesis rate increases substantially.
Moreover, macrophages accomplish this increased ATP syn-
thesis primarily through glycolysis with relatively little mitochon-
drial ATP synthesis contributing to this increased metabolic
activity. (c) Upregulation of glycolysis and glycolytic genes in
macrophages. Not all stimuli equally affect macrophage gly-
colysis; the classical pathway stimulation leads to an increase
in macrophage glycolysis, but alternative stimulation (such as
with IL4/IL13) does not. Classic or innate pathways result in the
upregulation of glucose uptake, the start of glycolysis (upper
left) and lactate production, a glycolytic end product (upper
right). Macrophage activation via the classic pathway triggers
an increase in the expression of glycolysis-associated genes
(lower left) and a reduction in the genes associated with the
tricarboxylicacidcycleandelectrontransportchain.Moreover,
classic stimulation leads to a shift in the expression of the
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2)
isoforms (lower right), from the liver type-PFK2 (L-PFK2), which
has a low net activity, to the more active ubiquitous-PFK2
(uPFK2), which maintains higher fructose-2,6-bisphosphate
(Fru-2,6-P2) concentrations due to minor bisphosphatase activ-
ity and, therefore, potentiates the glycolytic ﬂux. (d) High gly-
colytic ﬂux is required to prevent cell death in activated
macrophages. In classically stimulated macrophages, upregu-
lation of glycolysis is important to prevent cell death. In this
experiment, galactose, which is known to be effectively
metabolized in mitochondrial but not glycolytic ATP synthesis,
was used as a substrate. Although resting macrophages can
survive using mitochondrial ATP synthesis alone, classically acti-
vated macrophages die precipitously (yellow lines) when
deprived of the ability to utilize the glycolytic pathway. CpG
cytosine phosphate guanosine, LTA lipoteichoic acid (a –
Adapted from Rudd et al. [18], b – Adapted from Garedew
and Moncada [19], c – Adapted from Rodríguez-Prados et al.
[20], d – Adapted from Garedew et al. [21]).
X
Plasma
FDG
Glucose
Tissue
GLUT
FDG
Glucose
Hexokinase
G-6-phosphatase
Hexokinase
G-6-phosphatase Metabolic trapping
FDG-6-phosphate
Glycolysis
G-6-phosphate
a
b
Time, h
200
0
600
400
800
6
4
2
0
10
8
12
ATPsynthesisrate,pmolmiddots-1.10-6cells
TotalcellularATP,nmolmiddot10-6cells
Glycolytic ATP synthesis rate
Mitochondrial ATP synthesis rate
Total cellular ATP
0 3 6
IFNγ + LPS
9 12
*
*
*

c
2.5
2.0
1.5
1.0
0.5
LPS/IFNγ
LPS
Poly I:C
CpG
LTA
None
IL4/IL13
IL10
0 4 8 12
–1
–2
–3
1
0
2
Normalizedenrichmentscore
LPS/IFNγ
IL4/IL13
Glycolysis Pyruvate/
TCA cycle
Electron
transport chain
Time, h
0
Glucoseconsumption,µmol/mgprotein 4.5
3.0
1.5
LPS/IFNγ
LPS
Poly I:C
CpG
LTA
None
IL4/IL13
IL10
0 4 8 12
Time, h
0
Lactateproduction,µmol/mgprotein
**
0.032
0.455
0.243
*
0.097
0.547
0
***
–1
–2
–3
3
1
5
2
0
4
mRNAlevelsvsnon-stimulatedcells
LPS/IFNγ
IL4/IL13
pfkfb1
(L-PFK2)
pfkfb2
(heartPFK2)
pfkfb3
(uPFK2)
pfkfb4
(testisPFK2)
12 h
100
80
60
40
20
Control
Activated
0 12 24 36 48 7260
d
Time, h
0
Viability,%
Activation
Galactose
Medium
Glucose
Medium
FIGURE 12.10 (continued).

50
40
30
20
10
Macrophage layer
Necrosis
Granulation tissue
Tumor cells
01
a b
5 15 30 45 60
4
2
0
8
6
10
(18F)FDG,%ID/100µgprot.
Mac Glioma Panc AdenoCa
Time, min
0
Numberofgrains/100µm2
In vitro FDG uptake
FIGURE 12-11. Fluorodeoxyglucose uptake by macrophages is
important for tumor imaging and suggests that atherosclerosis
imaging should be feasible. (a) Several lines of evidence have
shown that FDG uptake of macrophages is important for tumor
imaging, such as that demonstrated by a radiomicrographic
study of intratumor FDG uptake over time in an animal model.
Although tumor cells consume an appreciable amount of FDG,
more than twice as much FDG localizes within macrophages
and necrotic regions. (b) It has been observed that FDG uptake
by macrophages (Mac) is similar to that seen by glioma and
pancreatic adenocarcinoma (Panc AdenoCa) cells. These
observations support the notion that at least part of the clinical
utility of FDG positron emission tomography (PET) imaging of
tumors can be attributed to FDG uptake by macrophages
(a – Adapted from Kubota et al. [22], b – Adapted from
Deichen et al. [23]).

40
20
0
80
100
120
60
140
FDGuptake,%ID/g*103
b
>5–15 >15Blood
activity
>0–5
Vessel inflammation, % RAM-11 staining
P < 0.001, r = 0.79
FIGURE 12-12. Distribution of deoxyglucose within atherosclerotic
plaques occurs predominantly in macrophages. (a)
Deoxyglucose accumulation within plaques co-localizes with
foam cell macrophages. The freshly excised and still live human
carotid atherosclerotic lesions were incubated in tritiated
deoxyglucose, followed by autoradiography and histopatho-
logic characterization. The radiolabel was primarily identified
within the lipid core of the atheroma, within foamy mac-
rophages [18]. (b) It was subsequently observed that FDG
uptake within the experimental atherosclerotic lesions corre-
lated with the severity of inflammation. In this rabbit atheroscle-
rotic model developed by balloon deendothelialization and
high-cholesterol diet; FDG was administered intravenously fol-
lowed by the assessment of lesional FDG uptake in comparison
with macrophage collection defined by RAM-11 staining. A
strong correlation is seen between inflammation and FDG
uptake in this animal model.

a c
5
4
3
2
0 10 20 48 40
Inflammation, % CD 68 staining
FDGuptake,T/B
b
Low uptake
1
PETTrichromeCD68 High uptake
r = 0.70
P < 0.001
10
8
6
4
2
r = 0.67
P = 0.03
1 2 3
SUVmax
IL-18
0
d
Foldexpression
6
4
2
1 2 3
SUVmax
Cathepsin K
0
e
Foldexpression
r = 0.77
P = 0.01
FIGURE 12-13. Fluorodeoxyglucose uptake correlates with plaque
inflammation in clinical imaging of carotid vascular disease.
(a) The hypothesis that arterial FDG uptake correlates with
plaque inflammation was also tested in patients with significant
carotid stenosis who were scheduled for carotid endarterec-
tomy. These patients were first imaged with FDG-PET, during
which FDG uptake within the carotid artery was quantified as
a target-to-background (T/B) ratio (a and b). Shortly after
imaging, the patients underwent carotid endarterectomy, at
which time carotid atheroma specimens were characterized
for CD 68 staining for macrophages and quantified mac-
rophage density within the same carotid lesions. A significant
correlation was observed between macrophage staining and
FDG uptake (c), confirming the information obtained from the
animal models. Additionally, FDG uptake has been shown to
correlate with the expression of genes associated with
inflammation, such as IL-18 (d) and cathepsin K (e). SUV stan-
dardized uptake value.

FIGURE 12-14. Fluorodeoxyglucose uptake and inflammation
vs. high-risk plaques. Increased FDG uptake observed in
symptomatic carotid disease is shown. CT angiographic
characteristics verified morphologic features in carotid
artery disease that are associated with a high risk of athero-
thrombosis, such as low-attenuation plaque (LAP), positive
remodeling (PR), and ulceration. (a) FDG uptake increases
within plaques that have high-risk morphologic features.
FDG uptake in two patients with significant carotid stenosis
is compared. The top panel depicts FDG and CT images of
a patient with high-risk morphology, whereas the bottom
panel shows images from a patient who had similarly severe
carotid stenosis and thus required carotid endarterectomy
but did not have any high-risk features. The intense FDG
uptake is associated with the high-risk carotid plaque,
whereas the patient in the panel below without it shows
minimal FDG uptake. (b) The cross-sectional PET-CT images
in the top row show high-risk CT angiographic features
(including positive remodeling, low-attenuation plaques,
and ulceration from the lumen into the plaques). The PET-CT
image shows increased FDG uptake in red localizing to the
low-attenuation plaque. Below the PET-CT images are
trichrome and macrophage (CD 68) staining of the same
lesion after it was removed during endarterectomy; endar-
terectomy shows a complex plaque with multiple lipid-rich
necrotic cores associated with intense CD 68 staining for
macrophages. The rightmost panels demonstrate that
inflammation assessed either by CD 68 staining for mac-
rophages or by PET-FDG uptake shows a graded increase
in inflammation along with an increase in the number of
high-risk morphologic features. (c) An FDG uptake study in
carotid vessel disease demonstrates intense tracer uptake
in the ipsilateral carotid lesions in a patient with recently
symptomatic disease. In contrast, the contralateral asymp-
tomatic carotid lesion has minimal FDG uptake. HRM high-
risk morphologic features, TBR target-to-background ratio
(a and b – Adapted from Figueroa et al. [24], c – Adapted
from Rudd et al. [25]).
(+)
HRM
(–)
HRM
a
CT, axial CT, coronal PET-CT, axial PET-CT, coronal

PET CT Fused image
Symptomatic
carotid stenosis
Asymptomatic
carotid stenosis
c
15
10
5
0
25
20
30
Histology,%CD68staining
0 1
P < 0.001 for trend
P < 0.001 for trend
2 3
0 1 2 3
Morphologic features
2
1
0
4
3
5
PET,TBR
CTandPET-CT
Low-powertrichrome
andCD68
High-power
CD68image
b
FIGURE 12-14. (continued).

Aorta
4
3
2
0
a
1
6
5
7
FDGuptake,TBR
ACS
3.30 (2.73–4.00)
Stable
2.43 (2.00–2.90)
P < 0.02
10
0.8
0.6
0.4
0.2
Mean TBR
<1.7 (n = 306; 91.6 %)
≥1.7 (n = 28; 8.4 %)
0
b
10 20 30 40
Time, months
0
Event-freesurvival
**P < 0.001
Framingham risk score
2
1
3
4
MaximumTBR
<10 % >20 %10–20 %
P = 0.001
P = 0.001 P = 0.284
c
FIGURE 12-15. Direct localization of inflammation for the risk
stratification of acute vascular events. (a) Aortic FDG uptake
may be found to be increased after ACS in the nonculprit vas-
culature, including the ascending aorta. It is hypothesized that
this is caused by the increased cytokine release that is seen after
atherothrombotic injuries such as myocardial infarction. This
figure demonstrates an increased metabolic activity in the aor-
tic root soon after ACS. (b) Elevated arterial FDG uptake identifies
an increased systemic risk of future atherothrombosis. In patients
evaluated for oncologic indications for whom subsequent fol-
low-up information was available, a relatively lower arterial FDG
uptake demonstrated higher event-free survival over the subse-
quent 40 months compared with patients with high FDG uptake.
These data demonstrate that assessment of arterial inflammation
in nonculprit arteries may provide prognostic information. (c) The
TBR levels of the arterial FDG signal increases with increasing
Framingham risk scores. Stratified by Framingham risk score,
patients with low risk (<10 %) show the lowest TBR and those with
a score greater than 20 show relatively higher TBR. Patients with
intermediate risk reveal a rather broad range for FDG uptake,
with substantial overlap between those with low and high
scores. It remains unknown whether the FDG uptake would be
useful for reclassifying patients with an intermediate Framingham
risk score into truly high- or truly low-risk categories. Carotid
plaque inflammation on FDG-PET predicts early stroke recur-
rence. In a study of 60 patients with recent stroke, a significantly
higher FDG signal was associated with patients who subse-
quently experienced a recurrence of stroke within 90 days (see
Table 12.1) (a – Adapted from Rogers et al. [26], b – Adapted
from Rominger et al. [27], c – Adapted from Kim et al. [28]).

a
1.1
1.0
0.9
0.8
0.7
0 7 14 21
1
0.8
0.6
0.2
0
0.4
1.6
1.2
1.8
1.4
2
MeanTBR
Scan 1
Scan 2
L-GC
GC
Ascending
aorta
Arch of
aorta
Descending
aorta
*
Abd
aorta
Left
carotid
Right
carotid
b
Time, days
0.6
Mean TBR in scan 1 and scan 2 by region
Relative SUV
10
8
6
4
9
7
5
3
2
1
No Rx Atorvastatin Simvastatin Mevastatin
c
0
P < 0.001
P < 0.001
P < 0.001RelativeSPECTsignal
FIGURE 12-16. Reproducibility of vascular 18
F-fluorodeoxyglucose
uptake and feasibility of demonstrating the efficacy of phar-
maceutical interventions. (a) The arterial FDG uptake signal is
relatively stable over a 1-month period in clinically stable
patients with atherosclerosis. The excellent reproducibility of
the signal was observed across several different vascular beds.
(b) Moreover, animal studies show that the arterial inflammatory
signal is rapidly modifiable using anti-inflammatory treatment.
In this particular case, the encapsulated glucocorticoid formu-
lation is associated with a substantial and rapid reduction in
inflammation (within 2 days after drug administration). (c)
Similarly, rapid modulation of atherosclerotic lesions has been
demonstrated using other targeting strategies. In this experi-
ment, radiolabeled monocytes are employed to target
inflamed atherosclerotic lesions. Pretreatment with any of three
statins results in a significant reduction in tracking of the radio-
labeled monocytes to the lesions, and such rapid tracking to
the aortic lesions is observed over 5–7 days. These data dem-
onstrate that atherosclerotic lesions are rapidly modified using
anti-atherosclerotic therapies. Abd abdominal, GC glucocorti-
coid, L-GC nanomedicinal formulation of glucocorticoid, Rx
treatment, SPECT single-photon emission CT (a – Adapted from
Rudd et al. [18], b – Adapted from Lobatto et al. [29], c –
Adapted from Kircher et al. [30]).

FIGURE 12-17. (a) The efficacy of statin therapy was first observed
in a single-center open-label study of simvastatin therapy vs.
dietary modification in patients undergoing FDG-PET imaging.
Over a 3-month period, the FDG uptake, measured as an SUV,
remained stable in patients who were randomly assigned to
diet alone, whereas a 10 % signal reduction was observed in
patients treated with low to moderate doses of simvastatin
[31]. (b) Similarly, pioglitazone therapy for 4 months resulted in
a significant reduction in the FDG signal, measured here as the
TBR. In contrast, glimepiride did not result in a reduction in PET
signal. Care was taken to keep fasting glucose levels similar
between patients randomly assigned to glimepiride and those
assigned to pioglitazone. A correlation also was observed
between changes in both high-density lipoprotein (HDL) and
C-reactive protein and the reduction in TBR signal [32]. (c) A
P38 mitogen-activated protein (MAP) kinase inhibitor similarly
reduced arterial inflammation in patients with atherosclerosis.
Patients with stable atherosclerosis were randomized to pla-
cebo vs. one of two doses of P38 MAP kinase inhibitors. At
baseline, patients were relatively well treated for the athero-
sclerosis, manifesting in low-density lipoprotein of 70 mg/dL
and baseline C-reactive protein of 1 mg/L. After 3 months of
treatment, there was a substantial but comparable reduction
in the arterial inflammatory signal with both inhibitors
compared with the placebo [33]. Interestingly, the same study
reported a substantial reduction in the FDG signal within vis-
ceral fat in patients treated with the higher dose of the P38
MAP kinase antagonist; there was no significant change in the
signal within subcutaneous fat (see Tables 12.2 and 12.3).
Visceral fat is known to be infiltrated by macrophages. (d)
Recently, the effect of the cholesteryl ester transport protein-
antagonist dalcetrapib was evaluated on arterial inflammation
as assessed by FDG-PET imaging. Although no significant treat-
ment effect on the overall arterial inflammatory signal was
observed, there was a significant relationship between
increases in HDL across all patients vs. changes in the
inflammatory signal [34]. (e) Further, the change in the PET sig-
nal at 6 months is associated with future changes in structural
measurements of the same arterial lesions at 24 months. The
patients who experienced an increase in their inflammatory
signal at 6 months tended to show a substantial progression of
total vessel area on MRI at 2 years, whereas patients who had
a decrease in the PET signal at 6 months revealed substantially
less remodeling on MRI at 24 months. These data provide pre-
liminary insights into a relationship between early inflammatory
changes and later structural changes within the same vessels.
BD twice a day, MDS most diseased segment, NS not significant,
OD once a day.
Diet Simvastatin
SUV
BaselineFollow-up
2.0
1.5
1.0
2.0
1.5
1.0
Baseline Post-
treatment
NS
Baseline Post-
treatment
P < 0.01
PET/CT
a

Pioglitazone Glimepiride Change in mean TBR from baseline
TBR
2.5
2.0
1.5
1.0
0.5
0
2.5
2.0
1.5
1.0
0.5
0
Baseline Post-
treatment
P < 0.01
Baseline Post-
treatment
NS P < 0.02
b
0
–0.1
–0.2
–0.3
–0.4
0.2
0.1
0.3
ΔTBR
Pioglitazone Glimepiride
–0.1
–0.2
0
0.05
–0.15
–0.25
–0.05
Changeinatherosclerosis
inflammation,ΔTBR
Placebo BDOD
P = 0.01
P = 0.02
c
–20
20
40
0
–40
ChangeinMDSTBR,
%increasefrombaseline
Tertile 1
(<1)
Tertile 3
(>12)
Tertile 2
(1–12)
R = –0.30, P = 0.04
Slope = 4.3%
d
e PET: change in MDS TBR at 6 months
0.06
0.04
0.02
0
0.10
0.08
0.12
MRI:changeinvesselareaat24months
Decrease Increase
FIGURE 12.17 (continued).

Group
1
0
2
3
4
5
FDGuptakeCoronaryPET-CT
ACS:
new stent
Stable syndrome:
new stent
Stable syndrome:
old stent
ACS:
new stent
Stable syndrome:
old stent
Stable syndrome:
new stent
P = 0.02
P = 0.006
FIGURE 12-18. Imaging of coronary artery inflammation. The fea-
sibility of molecular imaging has finally been demonstrated for
the assessment of inflammation in coronary vasculature. In a
recent study, patients presenting with ACS underwent an FDG-
PET imaging study and were compared with patients with sta-
ble coronary syndromes. CT imaging was obtained to identify
the culprit lesion in ACS or the target lesion in stable disease,
which was indicated by virtue of stent placement. As can be
appreciated here, the group of patients with recent ACS had
relatively high FDG uptake in association with the location of
the culprit lesion detected by the recently deployed stent. In
contrast, lower FDG signals were observed in association with
stents deployed for stable syndromes (Adapted from Rogers
et al. [26]).
Maximum SUV (SD) Day 84 vs. baseline Placebo and baseline corrected
Group Baseline Day 84 Difference 95 % CI P value Difference 95 % CI P value
HD (n=33) 0.32 (0.085) 0.30 (0.095) −0.02 −0.05, 0.00 0.060 −0.00 −0.04, 0.03 0.815
LD (n=32) 0.34 (0.084) 0.31 (0.079) −0.03 −0.05, 0.00 0.020 −0.01 −0.05, 0.03 0.636
Placebo (n=30) 0.34 (0.112) 0.32 (0.108) −0.02 −0.05, 0.01 0.168 NA NA NA
TABLE 12-2. The FDG signal in subcutaneous fat. HD high dose, LD low dose, NA not applicable.
Maximum SUV (SD) Day 84 vs. baseline Placebo and baseline corrected
Group Baseline Day 84 Difference 95 % CI P value Difference 95 % CI P value
HD (n=33) 0.59 (0.110) 0.53 (0.120) −0.06 −0.09, –0.02 0.002 −0.05 −0.09, –0.01 0.018
LD (n=32) 0.58 (0.133) 0.56 (0.140) −0.02 −0.06, 0.02 0.274 −0.02 −0.06, 0.03 0.502
Placebo (n=30) 0.57 (0.130) 0.57 (0.081) −0.01 −0.03, 0.02 0.654 NA NA NA
TABLE 12-3. The FDG signal in visceral fat. HD high dose, LD low dose, NA not applicable.
TABLE 12-1. Carotid plaque inflammation to predict early stroke recurrence. CCA common carotid artery, ICA internal
carotid artery (Adapted from Marnane et al. [35])
Maximum SUV, g/mL (SD)
Site of FDG uptake Stroke recurrence, n=13 No stroke recurrence, n=47 P value
Symptomatic ICA 2.87 (0.81) 2.37 (0.52) 0.01
Asymptomatic ICA 2.63 (0.62) 2.26 (0.41) 0.01
Symptomatic CCA 3.1 (0.56) 2.58 (0.52) 0.003

Arterial lumenBlood monocyte
MCP-1
CCR2
Monocyte adhered
to epithelium
Monocyte migrating
into intima
Dying
macrophage
Apoptotic
bodies
Macrophage
foam cell
Tissue
factor
Lipid
droplets
Modified
lipoprotein
particle
Scavenger
receptor
Adhesion
molecule
VCAM-1
Arterial intima
M-CSF
ROS
MMP
Cytokines
Monocyte becoming
intimal macrophage
FIGURE 12-19. Strategies for targeting of inflammation in athero-
sclerosis. Newer techniques will evolve that target the upregu-
lation of surface molecules or secreted products that are
uniquely expressed by the inflammatory cells associated with
unstable plaques. This road map identifies important targets for
molecular imaging. It will be important to identify atherosclero-
sis burden, based on the results of the PROSPECT (Providing
Regional Observations to Study Predictors of Events in the
Coronary Tree) trial published in the New England Journal of
Medicine in 2011. In addition, inflammation is a destabilizing
component of high-risk atherosclerotic lesions and therefore is
a high-reward molecular imaging target (see Table 12.4).
Although FDG is an attractive targeting tracer and offers global
information about vascular inflammation, newer radiotracers,
such as 18
F-4V or 11
C-PK11195, are emerging as promising tools.
A positron emission tomography tracer (18
F-4V) that reports on
vascular cell adhesion molecule (VCAM)-1, an adhesion mol-
ecule upregulated early in atherogenesis, may allow noninva-
sive detection of the system-wide burden of inflammatory
atherosclerosis [36]. Specific localization of high-risk coronary
plaques will greatly improve the efficiency of clinical trials test-
ing local therapies. For example, the recently described SECRITT
(Shield Evaluated at Cardiac Hospital in Rotterdam for
Investigation and Treatment of TCFA) trial employed multi-
modal structural imaging prior to prophylactic stent implanta-
tion [37]. For high-resolution molecular imaging of coronary
lesion inflammation, a near-infrared fluorescence (NIRF) molec-
ular imaging agent for coronary high-risk plaque detection is
the US Food and Drug Administration–approved agent indo-
cyanine green (ICG). Using intravascular NIRF sensing, ICG was
recently shown to target macrophages and lipids within exper-
imental and human plaques [38]. Further advances in molecu-
lar imaging of coronary lesions are expected with new
integrated NIRF-OCT catheters that allow simultaneous high-
resolution structural and molecular imaging [39]. CCR2
chemokine (CC motif) receptor 2, MCP monocyte chemoat-
tractant protein, M-CSF monocyte colony-stimulating factor,
MMP matrix metalloproteinase, ROS reactive oxygen species
(Adapted from Libby [40]).
Future Considerations
Targets
Modality VCAM Monocyte Lipid Protease MPO, ROS Apoptosis Angiogenesis
MRI + + + + + + +
PET/SPECT + + + + + + +
NIRF + + + + + + +
US + +
TABLE 12-4. Imaging agents for targets and imaging modalities.

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