beatriz isabel silva mendes
TRANSCRIPT
MESTRADOINTEGRADOEMMEDICINA–TRABALHOFINAL
BEATRIZISABELSILVAMENDES
Sodiumfluoride:howanoldmarkergainsanewmeaning
ARTIGODEREVISÃO
ÁREACIENTÍFICADECARDIOLOGIA
Trabalhorealizadosobaorientaçãode:
PROFESSORADOUTORAMARIAJOÃOSOARESVIDIGALTEIXEIRAFERREIRA
DR.MANUELDEOLIVEIRASANTOS
ABRIL/2019
SODIUM FLUORIDE: HOW AN OLD MARKER GAINS A NEW MEANING FLUORETO DE SÓDIO: COMO UM VELHO MARCADOR GANHA UM NOVO SIGNIFICADO
Autor: Beatriz Isabel Silva Mendesa – [email protected]
Orientador: Maria João Vidigal Ferreira, MD, PhDa,b,c – [email protected]
Co-orientador: Manuel de Oliveira Santos, MDa,b,c – [email protected]
(a) Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
(b) Serviço de Cardiologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
(c) Instituto de Ciências Nucleares Aplicadas à Saúde (ICNAS), Coimbra, Portugal
3
INDEX Contents
Abstract ................................................................................................................................. 4
Resumo ................................................................................................................................. 5
Acronyms and abbreviations list / Lista de acrónimos e abreviaturas .................................... 6
Introduction ........................................................................................................................... 7
Methods ................................................................................................................................ 8
Results .................................................................................................................................. 9
Table 1 – clinical studies of atherosclerosis and 18F-NaF ................................................. 11
Table 2 – clinical studies of aortic valve stenosis and 18F-NaF ......................................... 15
Discussion ........................................................................................................................... 16
New knowledge gained ....................................................................................................... 17
Agradecimentos .................................................................................................................. 17
References .......................................................................................................................... 18
Appendix I – results of search strategy diagram .................................................................. 22
4
ABSTRACT
Background. 18-Fluorine sodium fluoride is a well-known marker used for bone
metastasis diagnosis. Its uptake correlation with cardiovascular risk was primarily suggested
in oncological patients. Moreover, as a specific marker of microcalcification, it seems to
correlate with cardiovascular disease progression and plaque instability.
Methods and Results. Our purpose was to systematically review clinical studies that
characterized the use of this marker in cardiovascular conditions. In atherosclerosis, most
studies report a positive correlation with the burden of cardiovascular risk factors and
vascular calcification. A higher uptake was found in culprit plaques/rupture sites in coronary
and carotid arteries and it was also linked to high-risk features in histology and intravascular
imaging analysis of the plaques. In aortic stenosis, this tracer displayed an increasing uptake
with disease severity.
Conclusions. Sodium fluoride positron emission tomography is a promising non-
invasive technique to identify high-risk plaques, which sets ground to a potential use of this
tracer in evaluating atherosclerotic disease progression and degenerative changes in aortic
valve stenosis. Nevertheless, there is a need for further prospective evidence that
demonstrates this technique value in predicting clinical events, adjusting treatment strategies
and improving patient outcomes.
KEYWORDS
Positron emission tomography, sodium fluoride, cardiovascular risk, atherosclerosis,
aortic valve stenosis
5
RESUMO
Introdução. O fluoreto de sódio é um conhecido marcador usado no diagnóstico de
metástases ósseas. A correlação da captação do fluoreto de sódio com o risco
cardiovascular foi primeiramente sugerido em doentes oncológicos. Adicionalmente, como
marcador específico de microcalcificação, parece estar relacionado com a progressão da
doença cardiovascular e instabilidade da placa aterosclerótica.
Métodos e Resultados. Fizemos revisão sistemática de estudos clínicos que
caracterizaram o uso deste marcador em condições cardiovasculares. Na doença
aterosclerótica, a maior parte dos estudos descrevem uma correlação positiva com os
factores de risco cardiovasculares e calcificação vascular. Uma maior captação foi
encontrada em placas responsáveis por eventos agudos/locais de ruptura coronária e
carotídea, estando também ligado a características de alto risco em histologia e técnicas
intravasculares de análise da placa. Na estenose aórtica, este marcador mostrou um
aumento com a severidade da doença.
Conclusões. A tomografia de emissão de positrões é uma técnica não invasiva que
permite a identificação de placas de alto risco, nomeadamente através do uso do fluoreto de
sódio como marcador. Antevê-se o potencial deste marcador na avaliação da progressão da
doença aterosclerótica e de alterações degenerativas na válvula aórtica. Contudo, a
validação do uso clínico desta técnica ainda requer evidência prospectiva adicional que
demonstre o seu valor na estratificação de risco, adequação de estratégias de tratamento e
melhoria da sobrevida dos doentes.
PALAVRAS-CHAVE
Tomografia de emissão de positrões, fluoreto de sódio, risco cardiovascular,
aterosclerose, estenose da válvula aórtica
6
ACRONYMS AND ABBREVIATIONS LIST / LISTA DE ACRÓNIMOS E ABREVIATURAS
18F-NaF Fluorine-18 sodium fluoride Flúor-18 fluoreto de sódio
AAA Abdominal aortic aneurysm Aneurisma da aorta abdominal
AVS Aortic valve stenosis Estenose da válvula aórtica
CT Computed tomography Tomografia computorizada
CV Cardiovascular Cardiovascular
CVD Cardiovascular disease Doença cardiovascular
MI Myocardial infarction Enfarte do miocárdio
PET Positron emission tomography Tomografia de emissão de positrões
7
INTRODUCTION
Atherosclerotic cardiovascular (CV) events are the most common cause of death in
developed countries. Clinical diagnosis of atherosclerotic CV disease (CVD) is usually late
considering the atheroma pathogenesis process, mainly due to limitations in non-invasive
diagnosis of this multi-stage disease.
Plaque rupture and/or erosion are the main causes of acute clinical events. From
histologic and invasive clinical data, the culprit plaque tends to have a thin fibrous cap with
scarce smooth muscle cells, positive remodelling, large lipid-rich cores, high macrophage
content, luminal growing and microcalcifications.1 In addition, degenerative aortic valve
disease ultimately leads to hemodynamic stenosis of the valve with progressive leaflet
thickening, dystrophic calcification and increased rigidity.2 Therefore, microcalcification is one
of the key markers of plaque’s instability and degenerative changes in aortic valve stenosis
(AVS). However, due to the small diameter of the formed calcic vesicles, they cannot be
detected on routine computed tomography (CT), which only identifies macrocalcification
(200-500m in diameter).3
There is a non-invasive marker of the microcalcification process. In fields such as
oncology, fluorine-18 sodium fluoride (18F-NaF) is a positron-emitting radiotracer used for the
study of bone metabolism pathologies and bone metastasis.4 The high linkage affinity
between fluoride ions and the surface of calcic hydroxyapatite represents the main
biochemical principle for the identification of osteoblastic activity and new bone formation.5
The pattern of this tracer’s uptake depends on differences in regional blood flow, the density
of hydroxyapatite as well as exposed crystal surface area. 18F-NaF binds avidly to
microcalcification while areas of macrocalcification show only peripheral uptake thanks to its
large volume (low surface-area-to-volume ratio).3,6,7
This systematic review aims to summarize and consolidate 18F-NaF potentialities to
study CVD using positron emission tomography (PET).
8
METHODS
We systematically reviewed clinical studies with prospective/retrospective
methodology that looked into the use of 18F-NaF in CV conditions. All the in vivo clinical trials
made for CV purposes that correlated 18F-NaF activity with atherosclerotic disease, AVS and
abdominal aortic aneurysms (AAA), met the inclusion criteria. Only full original scientific
articles were included. We excluded any studies that did not meet all the inclusion criteria.
Additionally, we excluded trials only aiming to determine technical protocols for image
acquisition using 18F-NaF uptake.
In July of 2018, three separate searches were conducted for each group of
pathologies and their correlation with 18F-NaF, using PubMed, Embase and Cochrane
Library. The MeSH, Emtree and other additional terms “sodium fluoride”, “18f naf”, “18f
fluorine”, “fluorine 18”, “f naf”, “atherosclerosis”, “atheroma”, “atherosclerotic plaque”, “aortic
valve stenosis”, “aortic stenosis”, “aortic valve disease”, “valvular heart disease” and “aortic
aneurysm” in various combinations were used to build the research.
If relevant, additional articles were added to the screened records.
DATA COLLECTION
In the selected studies, the information concerning the following parameters was
collected: 1) imaging sites evaluated; 2) design/study type; 3) sampling inclusion criteria; 4)
number of patients; 5) injected in vivo dose of 18F-NaF measured in megabecquerel (MBq);
6) uptake period from intravenous administration to image acquisition; 7) study aim; 8)
number of patients with 18F-NaF uptake and positivity criteria; 9) results regarding 18F-NaF.
SUMMARY MEASURES
Target-to-background ratio (TBR) is calculated dividing the maximum standardized
uptake value (SUVmax) with blood pool SUV. Correspondently, SUVmax consists in the division
of the decay corrected tissue concentration of the tracer and the injected dose per
bodyweight; blood pool SUV is estimated as the mean of five regions of interest (ROI) in the
mid lumen of superior vena cava. Corrected uptake per lesion (CUL) can also be used,
subtracting the blood pool SUV from the SUVmax.
9
RESULTS
On the basis of the presented criteria, 31 articles were reviewed (Appendix I).
ATHEROSCLEROSIS
Twenty-five clinical studies looked into the use of 18F-NaF in the setting of
atherosclerosis (Table 1). In this matter, arterial wall 18F-NaF uptake was primarily assessed
in oncological patients that underwent PET/CT imaging. The majority of these retrospective
studies showed a positive correlation of this marker with calcification and the number of CV
risk factors.8-14 For instance, in a retrospective analysis of over 400 patients by Janssen et
al., 18F-NaF uptake in the femoral arteries increased with the amount of CV risk factors and
the calcified plaques per patient.12 Furthermore, baseline 18F-NaF uptake significantly
correlated with calcification progression and Agaston score in a CT performed one year
after.14
Prospective studies were subsequently carried out on populations that met CV
inclusion criteria or with known CVD. Four studies performed in patients with different risk
profiles demonstrated that 18F-NaF uptake increases with the number of CV risk factors.15-18
In a prospective analysis of 89 healthy subjects with low CV risk, Blomberg et al. showed that
the estimated future risk for CVD development increases linearly with coronary 18F-NaF
accumulation.17 Our group studied patients with high CV risk, examining 18F-NaF uptake in
the major arterial territories (coronary, aorta, carotid), and found similar correlations with risk
factors, including thoracic fat volume.15,16 Other five studies looked into 18F-NaF uptake in
patients with known/suspected CVD and showed that this marker is able to identify high-risk
atherosclerotic plaques and culprit lesions.7,19-22 Within this group, Dweck et al. conducted
the first feasibility study on the coronary arteries and found a higher uptake in patients with
coronary atherosclerosis.19 Later, Joshi et al. prospectively studied the coronary and carotid
arteries of patients with myocardial infarction (MI), stable angina and symptomatic carotid
artery disease.7 In this landmark report, 37 out of 40 patients with MI had higher uptake in
culprit plaques, which were 34% more intense than non-culprit sites.7 Moreover, superior 18F-
NaF uptake was linked to high-risk features identified in endarterectomy specimens
histology.7 Subsequently, Lee et al. used intravascular ultrasonography and optical
coherence tomography techniques in stable coronary heart disease patients to validate these
findings, correlating 18F-NaF uptake with high-risk features assessed in vivo.21 Remarkably,
93% of the lesions that met high-risk criteria in both techniques showed 18F-NaF uptake.21
In cerebrovascular disease population, symptomatic and culprit carotid lesions also
showed a significant correlation with 18F-NaF uptake.6,23,24 The use of advanced techniques
(histological marking and micro PET/CT) supported previous clinical observations, showing a
10
strong correlation of 18F-NaF uptake with calcification markers (alizarin red staining) and with
clinically symptomatic plaques.6,25
The concept of micro- and macrocalcification differentiation was studied by Irkle et al.
in a complementary in vivo and ex vivo analysis.3 Firstly, in vivo PET imaging in symptomatic
patients scheduled to undergo carotid endarterectomy explored the pharmacodynamic and
pharmacokinetic properties of 18F-NaF, where this tracer showed conducive imaging
properties with excellent tissue contrast resolution.3 Besides, cellular specificity of 18F-NaF
binding was histologically correlated with markers of calcification, but not with macrophages,
neovascularization and smooth muscle markers.3 Moreover, 18F-NaF signal was compared
with sectioned carotid tissue micro- and macrocalcification in μPET/μCT, with its binding
increased in microcalcifications (<50μm) and detected only on the outer surface layer of
macrocalcific deposits.3
AORTIC STENOSIS
Four clinical studies looked into the use of 18F-NaF in AVS (Table 2). The first
feasibility study concluded that there is an intense uptake of this marker in patients with
known AVS.26 Further reports demonstrated 18F-NaF ability to mark different disease stages
and described this tracer’s accumulation in proportion with calcium scores, blood and
histological markers of calcification and disease progression.27-29 In fact, 18F-NaF uptake was
associated with disease severity and correlated with histological markers of active
calcification.27-29 Dweck et al. reported a positive uptake (TBRmax>1.97) in 100% of severe,
95% of moderate and 76% of mild AVS.27 18F-NaF uptake was also a good predictor of
disease progression by CT calcium score after one year, with concordant distribution of new
calcic deposits in regions with previous radiotracer accumulation.29
OTHER APPLICATIONS
In a study by Forsythe et al., 18F-NaF uptake was increased in AAA compared to non-
aneurysmal regions within the same aorta and co-localized with areas of aneurysmal disease
activity and active calcification.30 Moreover, 18F-NaF uptake is likely a major predictor of
aneurysm expansion (over twice the expansion rate in the highest tertile of uptake), showing
three times higher risk of repair or rupture in the highest tertile of uptake.30
A small clinical study assessed whether 18F-NaF could determine Takayasu arteritis
disease grade and evaluate its progression.31 There was a correlation between 18F-NaF
uptake and different stages of metabolic disease.31
In patients with recent MI, 18F-NaF accumulation was significantly higher in scar
tissue than in healthy myocardium.22
11
Tabl
e 1
– C
linic
al stu
die
s o
f ath
ero
scle
rosis
and 1
8F
-NaF
Stud
y/A
utho
rs
Year
* Si
te
Des
ign/
Stud
y Ty
pe
Incl
usio
n C
riter
ia
Patie
nt
Num
ber
Dos
e (M
Bq)
U
ptak
e Pe
riod
(min
)
Aim
Pr
imar
y O
utco
me
Mea
sure
/Pre
vale
nce
(Pat
ient
s)
Res
ults
ON
CO
LOG
ICA
L PO
PULA
TIO
NS
Der
lin e
t al.8
201
0
Majo
r art
erie
s
Retr
osp
ective
P
revio
us 1
8F
-N
aF
PE
T/C
T f
or
bon
e
meta
sta
ses
75
350±
50
60
A
rteri
al
18F
-Na
F u
pta
ke
corr
ela
tion
with
calc
ific
atio
n
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/5
7 (
76%
)
88%
of th
e lesio
ns w
ith 1
8F
-Na
F u
pta
ke
sho
wed c
alc
ific
atio
n.
Beh
esht
i et a
l.32
201
1
Heart
and
aort
a
Retr
osp
ective
P
revio
us 1
8F
-N
aF
PE
T/C
T f
or
malig
na
ncy
51
370
-550
60
D
egre
e a
nd p
revale
nce
of
18F
-Na
F u
pta
ke a
s
calc
ific
atio
n e
vid
ence in
ath
ero
scle
rotic p
laqu
es
with n
orm
al agin
g
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
Card
iac a
nd a
ort
ic 1
8F
-Na
F u
pta
ke a
nd
deg
ree o
f calc
ific
ation
co
rrela
ted
sig
nific
antly w
ith
age.
Der
lin e
t al.9
201
1
Majo
r art
erie
s
Retr
osp
ective
P
revio
us 1
8F
-N
aF
PE
T/C
T in
oncolo
gic
patients
45
350±
50
60
C
om
pari
so
n b
etw
een 1
8F
-N
aF
an
d 1
8F
-FD
G u
pta
ke
and
co
rrela
tio
n w
ith C
PB
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/2
7 (
60%
)
77.1
% o
f th
e lesio
ns w
ith
18F
-Na
F u
pta
ke
sho
wed c
alc
ific
atio
n.
Der
lin e
t al.1
0 201
1
Caro
tid
art
erie
s
Retr
osp
ective
P
revio
us 1
8F
-N
aF
PE
T/C
T f
or
bon
e
meta
sta
ses
269
350±
50
60
C
orr
ela
tion
be
twe
en 1
8F
-N
aF
up
take in t
he
com
mon c
aro
tid a
rteri
es,
CV
ris
k facto
rs a
nd C
PB
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/9
4 (
34.9
%)
18F
-Na
F u
pta
ke a
nd c
alc
ific
atio
n c
o-
localiz
ed a
t all
site
s a
nd w
ere
hig
hly
corr
ela
ted
. H
igh c
orr
ela
tion
be
twe
en 1
8F
-N
aF
up
take a
nd
the
num
ber
of
CV
ris
k
facto
rs,
ag
e, m
ale
se
x,
hyp
ert
ensio
n a
nd
hyp
erc
hole
ste
role
mia
.
Li e
t al.1
1 201
2
Majo
r art
erie
s
and
coro
na
ry
art
erie
s
Retr
osp
ective
P
revio
us 1
8F
-N
aF
PE
T/C
T f
or
bon
e s
tudie
s
61
370±
74
40
V
ascula
r 18F
-NaF
upta
ke
associa
tio
n w
ith v
ascula
r calc
ific
atio
n a
nd C
HD
TB
R≥1.5
in
all
ort
hog
on
al im
ag
e
pla
nes/5
9 (
97%
)
18F
-Na
F u
pta
ke
po
sitiv
ely
co
rrela
ted w
ith
calc
ific
atio
n a
nd h
isto
ry o
f C
V e
ve
nts
. N
eith
er
the
indiv
idu
al C
V r
isk e
stim
atio
n
nor
the n
um
be
r of
risk facto
rs c
orr
ela
ted
with c
oro
na
ry u
pta
ke.
Jans
sen
et a
l.12
201
3
Fem
ora
l art
erie
s
Retr
osp
ective
P
revio
us 1
8F
-N
aF
PE
T/C
T in
oncolo
gic
patients
409
350±
50
60
Lin
ear
18F
-NaF
up
take
corr
ela
tion
with
CV
ris
k
facto
rs a
nd C
PB
Unifo
rm lin
ear
railr
oa
d
track-t
yp
e t
racer
upta
ke
>
two-t
hir
ds t
he v
essel's
le
ng
th/1
59
(38.9
%)
Sig
nific
ant
corr
ela
tio
n b
etw
ee
n 1
8F
-Na
F
upta
ke a
nd a
ge,
hyp
ert
ensio
n,
hyp
erc
hole
ste
role
mia
, dia
bete
s, his
tory
of
sm
okin
g, p
rior
CV
even
ts a
nd C
PB
. Lin
ear
18F
-Na
F u
pta
ke incre
ase
d w
ith
th
e n
um
ber
of C
V r
isk facto
rs a
nd t
he n
um
ber
of
calc
ifie
d p
laq
ues p
er
patient.
Kur
ata
et a
l.13
201
3
Majo
r art
erie
s
Retr
osp
ective
O
ncolo
gic
patients
with
18F
-Na
F P
ET
/CT
fo
r bo
ne
meta
sta
ses
29
≈185
60
E
valu
ation
of
18F
-NaF
upta
ke p
revale
nce,
dis
trib
ution,
an
d
rela
tion
ship
with
art
eri
al
calc
ific
atio
n
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/8
(28%
)
91%
of th
e lesio
ns w
ith 1
8F
-Na
F u
pta
ke
sho
wed c
alc
ific
atio
n.
Only
10%
of th
e
calc
ifie
d le
sio
ns s
ho
we
d in
cre
ased 1
8F
-N
aF
up
take. A
rteri
al u
pta
ke a
nd
calc
ific
atio
n s
ignific
antly a
ssocia
ted
with
age
. M
orbe
lli e
t al.3
3 201
4
Majo
r art
erie
s
Pro
sp
ective
O
ncolo
gic
patients
und
erg
oin
g 1
8F
-N
aF
PE
T/C
T f
or
bon
e
meta
sta
ses
80
370
60
18F
-Na
F u
pta
ke
corr
ela
tion
with
F
ram
ingh
am
ris
k facto
rs
and
CP
B
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
18F
-Na
F u
pta
ke s
ignific
antly c
orr
ela
ted
with a
ge,
hyp
ert
ensio
n, sm
okin
g a
nd
dia
bete
s. V
isib
le c
alc
ium
dep
ositio
n
dep
en
de
d o
nly
on a
ge
. N
o c
orr
ela
tion
betw
ee
n r
egio
nal calc
ium
loa
d a
nd
TB
R.
12
Fiz
et a
l.34
201
5
Infr
are
nal
abd
om
inal
aort
a
Pro
sp
ective
O
ncolo
gic
patients
und
erg
oin
g 1
8F
-N
aF
PE
T/C
T f
or
bon
e
meta
sta
ses w
ith
≥1 a
rte
rial
calc
ific
atio
n in
the infr
are
nal
abd
om
inal ao
rta
64
4.8
-5.2
/kg o
f bod
y w
eig
ht
60-7
5
18F
-Na
F u
pta
ke
evalu
ation in d
iffe
ren
t pla
que d
ensity
calc
ific
atio
n a
nd w
he
the
r atte
nu
atio
n w
eig
hte
d
image r
econstr
uctio
n
affecte
d 1
8F
-Na
F u
pta
ke
valu
es in t
he d
iffe
ren
t pla
que s
tages
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
Inve
rse
co
rrela
tio
n b
etw
ee
n 1
8F
-Na
F
upta
ke a
nd d
ensity o
f calc
ific
ation
.
Ishi
wat
a et
al.1
4 201
7
Majo
r art
erie
s
Retr
osp
ective
M
alig
na
ncy o
r ort
hop
ae
dic
dis
ea
se p
atients
w
ith w
hole
-bod
y
18F
-Na
F P
ET
/CT
and
an
une
nh
anced C
T
app
roxim
ate
ly 1
ye
ar
aft
er
adm
issio
n
34
185
40
V
ascula
r 18F
-NaF
upta
ke
corr
ela
tion
with
CT
calc
ium
score
pro
gre
ssio
n
1.5
SU
Vm
ax c
ut-
off/N
ot
describ
ed
18F
-Na
F u
pta
ke s
ignific
antly c
orr
ela
ted
with c
alc
ific
ation
pro
gre
ssio
n, volu
metr
ic
score
and p
rog
ressio
n in A
gasto
n s
co
re.
Li e
t al.3
5 201
7
Majo
r art
erie
s
Retr
osp
ective
M
ultip
le
mye
lom
a
patients
with
18F
-Na
F P
ET
/CT
fo
r bo
ne
meta
sta
ses
34
310
-380
N
ot
describ
ed
18F
-Na
F a
nd 1
8F
-FD
G
upta
ke a
ssocia
tion w
ith
pla
que d
ensity
calc
ific
atio
n a
nd d
ise
ase
pro
gre
ssio
n
1.8
TB
R f
or
po
sitiv
e
oste
og
ene
sis
/Not
describ
ed
Hig
he
r 18F
-Na
F u
pta
ke in n
on
-calc
ifie
d
and
severe
ly c
alc
ifie
d le
sio
ns a
nd lo
we
r upta
ke in m
ildly
calc
ifie
d p
laque
s. D
urin
g
follo
w-u
p,
18F
-Na
F u
pta
ke incre
ased
with
calc
ium
density.
SUB
CLI
NIC
AL
ATH
ERO
SCLE
RO
SIS
Dw
eck
et a
l.19
201
2
Coro
na
ry
art
erie
s
Pro
sp
ective
C
ontr
ol subje
cts
and
pa
tien
ts a
ge
d
>50 y
ea
rs w
ith
aort
ic s
cle
rosis
and
m
ild, m
ode
rate
and
seve
re A
VS
119
124±
10
66±6
18F
-Na
F a
nd 1
8F
-FD
G
PE
T/C
T u
pta
ke a
s
mark
ers
of active
calc
ific
atio
n a
nd
inflam
matio
n,
respectively
TB
Rm
ax>
1.4
5 (
hig
her
contr
ol gro
up
valu
e)/
34%
Hig
he
r 18F
-Na
F u
pta
ke in p
atients
with
coro
na
ry a
thero
scle
rosis
. S
tron
g
corr
ela
tion
be
twe
en t
he
CC
S a
nd
18F
-NaF
upta
ke, altho
ugh
41%
of
pa
tien
ts w
ith
C
CS
>1,0
00 h
ad n
o s
ignific
ant
upta
ke.
Hig
he
r F
ram
ingh
am
ris
k s
co
res in p
atie
nts
w
ith in
cre
ase
d 1
8F
-Na
F u
pta
ke. 1
0 y
ear
Fra
min
gh
am
ris
k s
co
res fo
r C
VD
, C
VD
dea
th a
nd C
HD
de
ath
co
rrela
ted w
ith 1
8F
-N
aF
coro
nary
up
take b
ut
not
with
CC
S.
Ferr
eira
et a
l.15
201
7
Caro
tid
art
erie
s,
coro
na
ry
art
erie
s
and
ao
rta
Pro
sp
ective
A
sym
pto
matic
patients
ag
ed
>40
ye
ars
with h
igh C
V
risk w
itho
ut kno
wn
CV
D
25
2.5
/kg o
f bod
y w
eig
ht
(18
5)
60
18F
-Na
F u
pta
ke
evalu
ation w
ithin
th
e
art
erial w
all
in h
igh C
V
risk p
atie
nts
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/2
4 (
96%
)
TB
R b
ut
not
CU
L is h
ighe
r in
men t
han in
wom
en w
hile
CU
L b
ut
not T
BR
is r
ela
ted
to t
he n
um
ber
of C
V r
isk facto
rs.
Oliv
eira
-San
tos
et
al.16
201
7
Caro
tid
art
erie
s,
coro
na
ry
art
erie
s
and
ao
rta
Pro
sp
ective
A
sym
pto
matic
patients
ag
ed
>40
ye
ars
with h
igh C
V
risk w
itho
ut kno
wn
CV
D
25
185
60
C
orr
ela
tion
of
18F
-NaF
upta
ke in h
igh C
V r
isk
part
icip
ants
with C
V r
isk
facto
rs,
CC
S a
nd t
hora
cic
fa
t volu
me
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/9
6%
in a
ort
a;
40%
in
ca
rotid a
rte
ries;
64%
in
co
ronary
art
erie
s
Patien
ts w
ith ≥
5 r
isk facto
rs (
60%
) h
ad
incre
ased 1
8F
-NaF
upta
ke; th
e latte
r w
as
positiv
ely
corr
ela
ted w
ith
pre
dic
ted f
ata
l C
V r
isk. N
o c
orr
ela
tio
n b
etw
een
18F
-Na
F
upta
ke in c
oro
na
ry a
rteri
es a
nd c
alc
ium
score
. M
odera
te c
orr
ela
tion b
etw
ee
n C
UL
and
th
ora
cic
fat.
13
Blo
mbe
rg e
t al.1
7 201
7
Coro
na
ry
art
erie
s
Pro
sp
ective
H
ealth
y s
ubje
cts
w
ith lo
w C
V r
isk
89
2.2
/kg o
f bod
y w
eig
ht
(17
4±3
9)
92±4
C
oro
na
ry a
rtery
18F
-NaF
upta
ke c
orr
ela
tio
n w
ith
C
V r
isk
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
In h
ealth
y a
dults, se
x,
ag
e a
nd
BM
I are
in
de
pe
nd
ent
dete
rmin
ants
of
co
ronary
18F
-N
aF
up
take. C
oro
na
ry 1
8F
-Na
F u
pta
ke
incre
ased lin
ea
rly w
ith
the n
um
ber
of C
V
risk facto
rs. T
he e
stim
ate
d 1
0-
and 3
0-
ye
ar
risk o
f C
VD
incre
ase
d lin
ea
rly w
ith
th
e c
oro
nary
18F
-NaF
upta
ke.
Blo
mbe
rg e
t al.1
8 201
7
Thora
cic
aort
a
Pro
sp
ective
Lo
w C
VD
ris
k
pop
ula
tion:
patie
nts
w
ith c
hest
pain
synd
rom
es a
nd
health
y v
olu
nte
ers
139
2.2
/kg o
f bod
y w
eig
ht
(17
4±3
5)
91±4
C
om
pari
so
n b
etw
een 1
8F
-N
aF
an
d 1
8F
-FD
G u
pta
ke
and
co
rrela
tio
n w
ith
vascula
r calc
ium
bu
rden
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
18F
-Na
F u
pta
ke
po
sitiv
ely
co
rrela
ted w
ith
C
T c
alc
ium
burd
en
and h
igher
CV
D r
isk.
CO
RO
NA
RY
AR
TER
Y D
ISEA
SE
Josh
i et a
l.7
201
4
Coro
na
ry
and
ca
rotid
art
erie
s
Pro
sp
ective
P
atien
ts w
ith p
re-
esta
blis
hed M
I or
sta
ble
angin
a a
nd
patients
und
erg
oin
g c
aro
tid
end
art
ere
cto
my fo
r sym
pto
matic
dis
ea
se
89
123
60
R
uptu
red a
nd h
igh-r
isk
ath
ero
scle
rotic p
laqu
es
iden
tification
usin
g 1
8F
-N
aF
an
d 1
8F
-FD
G
TB
R>
25%
th
an a
pro
xim
al re
fere
nce
lesio
n/3
7 o
f 40
(93%
) w
ith M
I in
th
e c
ulp
rit
pla
que;
18
of
40
(45%
) w
ith s
table
CH
D
93%
MI culp
rit pla
que
s s
ho
wed
incre
ased
18F
-Na
F,
34%
hig
he
r in
culp
rit
pla
que
s
tha
n th
e m
axim
um
activity a
nyw
here
els
e
in th
e c
oro
na
ry v
ascula
ture
. H
igh 1
8F
-NaF
upta
ke in a
ll ca
rotid p
laq
ue r
uptu
re s
ite
s
whic
h h
ad h
igh
er
calc
ific
atio
n a
ctivity,
macro
pha
ge
infiltra
tion a
nd c
ell
death
. 18F
-Na
F u
pta
ke in
pla
que
s o
f sta
ble
angin
a p
atien
ts w
as m
ostly n
on-
obstr
uctive (
<7
0%
ste
no
sis
) an
d h
ad
hig
h-
risk featu
res:
positiv
e r
em
odelli
ng,
mic
rocalc
ific
ation a
nd n
ecro
tic c
ore
.
Kita
gaw
a et
al.2
0 201
7
Coro
na
ry
art
erie
s
Pro
sp
ective
K
no
wn
or
susp
ecte
d C
HD
w
ith ≥
1 c
oro
nary
ath
ero
scle
rotic
lesio
n d
ete
cte
d o
n
CC
TA
in s
egm
ents
>
2m
m in d
iam
ete
r
32
370
60
18F
-Na
F P
ET
/CT
upta
ke
corr
ela
tion
with
CT
coro
na
ry a
thero
scle
rosis
Fo
r e
ach
ath
ero
scle
rotic lesio
n,
a
RO
I w
as d
raw
n in
a
pro
xim
al re
fere
nce s
ite
witho
ut pla
que t
o
calc
ula
te t
he c
ontr
ol
TB
Rm
ax/N
ot
describ
ed
CC
S c
orr
ela
ted p
ositiv
ely
with c
oro
na
ry
18F
-Na
F u
pta
ke.
MI
or
unsta
ble
angin
a
his
tory
and
co
ronary
pla
qu
es w
ith C
CT
A-
iden
tifie
d h
igh
-ris
k fea
ture
s s
ho
wed
hig
her
coro
na
ry 1
8F
-NaF
upta
ke.
Lee
at a
l.21
201
7
Coro
na
ry
art
erie
s
Pro
sp
ective
S
uspe
cte
d C
HD
patients
with 1
8F
-N
aF
PE
T p
rio
r to
in
vasiv
e c
oro
na
ry
angio
gra
ph
y
51
3/k
g o
f bo
dy
weig
ht
60
18F
-Na
F P
ET
/CT
clin
ical
rele
van
ce e
valu
ation
usin
g O
CT
, IV
US
an
d
CC
TA
in p
atie
nts
with
CH
D
Pla
qu
es w
ith u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
Pla
qu
es w
ith 1
8F
-Na
F u
pta
ke s
ho
we
d
hig
her
pla
qu
e b
urd
en
, m
ore
fre
que
nt
poste
rior
atte
nu
atio
n a
nd
positiv
e
rem
od
elli
ng in I
VU
S a
nd h
igher
ma
xim
um
lip
id a
rc a
nd m
ore
mic
rovessels
in O
CT
. 94.1
%18F
-NaF
po
sitiv
e lesio
ns h
ad ≥
1
hig
h-r
isk fe
atu
res. 9
3.3
% h
igh-r
isk lesio
ns
sho
wed 1
8F
-NaF
up
take.
Mar
ches
seau
et a
l.22
201
7
Coro
na
ry
art
erie
s
and
m
yocard
ial
tissue
Pro
sp
ective
S
TE
MI pa
tien
ts
und
erg
oin
g p
rim
ary
perc
uta
ne
ou
s
coro
na
ry
inte
rve
ntio
n
10
PE
T/
MR
; 8
PE
T/
CT
PE
T/M
R:
2.9
5±0.2
1
mC
i;
PE
T/C
T: not
describ
ed
PE
T/M
R:
60-7
5;
PE
T/C
T:
108±
21
18F
-Na
F P
ET
/CT
valid
ation
fo
r th
e
dete
ctio
n o
f hig
h-r
isk
coro
na
ry a
thero
ma a
nd
PE
T/M
R q
uan
tifica
tion
of
the u
pta
ke in m
yo
ca
rdia
l health
y a
nd s
car
tissu
e
1.7
0 T
BR
th
reshold
to
hig
h a
nd lo
w-r
isk
lesio
ns/N
ot d
escri
be
d
TB
R o
f culp
rit
lesio
ns h
ighe
r th
an n
on-
culp
rit. T
BR
hig
her
in s
car
tissu
e t
han
in
health
y m
yo
ca
rdiu
m.
14
CER
EBR
OVA
SCU
LAR
DIS
EASE
Qui
rce
et a
l.23
201
3
Caro
tid
art
erie
s
Pro
sp
ective
P
atien
ts w
ith ≥
1
pla
que d
ete
cte
d b
y
contr
ast C
T d
urin
g
a n
euro
logic
al
work
-up
15
370
180
18F
-Na
F u
pta
ke
corr
ela
tion
an
d
iden
tification
in c
aro
tid
art
erie
s a
nd p
revio
usly
id
en
tifie
d c
alc
ifie
d
pla
ques
Pla
qu
es w
ith u
pta
ke,
reg
ard
less th
e
inte
nsity/1
00%
All
pla
ques r
eve
ale
d s
om
e d
egre
e o
f upta
ke. T
he p
laque
s o
f th
e s
ym
pto
matic
gro
up h
ad h
igh
er
upta
ke.
Irkle
et a
l.3
201
5
Caro
tid
ath
ero
ma
P
rosp
ective
P
atien
ts
und
erg
oin
g c
aro
tid
end
art
ere
cto
my fo
r sym
pto
matic
ste
nosis
4
250
60
A
ctive v
ascula
r m
icro
calc
ific
ation
iden
tification
by 1
8F
-NaF
P
ET
/CT
Not d
escribe
d
Hig
he
r upta
ke
re
gio
ns in
th
e a
bse
nce
of
calc
ium
on C
T,
repre
sen
tin
g
mic
rocalc
ific
ation (
<5
0μ
m).
Larg
e C
T-
dete
cte
d a
reas o
f m
acro
calc
ific
atio
n
witho
ut u
pta
ke.
Hig
her
18F
-Na
F a
ctivity o
n
the s
urf
ace o
f m
acro
scopic
calc
ic d
epo
sits
and
no
t w
ithin
their
core
.
Qui
rce
et a
l.24
201
6
Caro
tid
ath
ero
ma
P
rosp
ective
R
ece
nt str
oke
9
370
180
C
om
pari
so
n b
etw
een 1
8F
-N
aF
an
d 1
8F
-FD
G u
pta
ke
in s
ym
pto
matic a
nd n
on
-sym
pto
matic p
laqu
es
Pla
qu
es w
ith u
pta
ke,
reg
ard
less th
e
inte
nsity/1
00%
18F
-Na
F u
pta
ke h
ighe
r th
an
18F
-FD
G in 1
1
of th
e 1
8 p
laque
s.
Hig
he
r m
ean T
BR
in
th
e s
ympto
ma
tic g
roup
. In
sym
pto
ma
tic
pla
ques,
18F
-Na
F u
pta
ke s
ho
wed
an
invers
e c
orr
ela
tio
n w
ith c
alc
ium
burd
en
.
Vese
y et
al.6
201
7
Caro
tid
ath
ero
ma
P
rosp
ective
R
ece
nt tr
ansie
nt
ischem
ic a
tta
ck o
r m
inor
ischem
ic
str
oke: culp
rit
caro
tid s
tenosis
a
waitin
g
end
art
ere
cto
my
and
co
ntr
ols
w
itho
ut culp
rit
caro
tid a
thero
ma
26
244
.5±1
2.6
6
64.5
±5.6
C
om
pari
so
n b
etw
een 1
8F
-N
aF
an
d 1
8F
-FD
G u
pta
ke
abili
ty t
o ide
ntify
culp
rit
and
hig
h-r
isk c
aro
tid
pla
ques
Pla
qu
es w
ith u
pta
ke,
reg
ard
less th
e
inte
nsity/N
ot
describ
ed
On h
isto
logic
al a
nd m
icro
PE
T/C
T
analy
sis
, 18F
-NaF
sele
ctively
id
entified
mic
rocalc
ific
ation.
Hig
her
18F
-Na
F u
pta
ke
in c
linic
ally
adju
dic
ate
d c
ulp
rit
pla
qu
es.
18F
-Na
F u
pta
ke c
orr
ela
ted w
ith h
igh
-ris
k
pla
que f
ea
ture
s,
pla
qu
e b
urd
en a
nd
pre
dic
ted C
V r
isk.
Zhan
g et
al.2
5 201
8
Caro
tid
art
erie
s
Pro
sp
ective
S
ympto
matic
patients
und
erg
oin
g c
aro
tid
end
art
ere
cto
my fo
r caro
tid a
rtery
ste
nosis
(<
70%
)
8
4.4
4/k
g o
f bod
y w
eig
ht
60
18F
-Na
F u
pta
ke
corr
ela
tion
with
his
tolo
gic
al
chara
cte
rizatio
n o
f vascula
r calc
ific
ation in
caro
tid p
laque
s
Segm
ents
with u
pta
ke,
reg
ard
less th
e
inte
nsity/1
00%
in t
he
bila
tera
l ca
rotid
bifurc
ation
Str
on
g c
orr
ela
tion
betw
een 1
8F
-NaF
upta
ke a
nd a
lizari
n r
ed s
tain
ing -
calc
ific
atio
n m
ark
er.
No c
orr
ela
tio
n w
ith
C
D68 s
tain
ing
-in
flam
matio
n m
ark
er-
and
alp
ha-s
mo
oth
muscle
actin
sta
inin
g -
sm
ooth
muscle
mark
er.
No c
orr
ela
tio
n
with c
aro
tid a
rtery
ste
nosis
, H
U v
alu
e o
r in
flam
matio
n.
18F
-NaF
, fluori
ne
-18
sodiu
m flu
orid
e;
18F
-FD
G,
flu
orin
e-1
8 f
luoro
-deoxy-g
lucose
; C
CS
, coro
nary
calc
ium
score
; C
CT
A, coro
nary
CT
ang
iogra
ph
y; C
HD
, coro
nary
heart
dis
ease;
CP
B, calc
ifie
d p
laque
burd
en;
CT
, com
pute
d tom
ogra
ph
y;
CU
L, corr
ecte
d u
pta
ke p
er
lesio
n; C
V, card
iovascu
lar;
CV
D, card
iovascu
lar
dis
ease;
HU
, H
ounsfie
ld u
nit;
IVU
S, in
tra
vascula
r ultra
sound; m
CI, m
illic
uri
e;
MI,
myocard
ial in
farc
tion;
MR
, m
agnetic r
esonance; O
CT
, optica
l coh
ere
nce
tom
ogra
ph
y;
PE
T, positro
n e
mis
sio
n tom
ogra
ph
y;
RO
I, r
egio
n o
f in
tere
st; S
TE
MI, S
T-e
leva
tion m
yocard
ial in
farc
tion;
SU
V, sta
ndard
ized u
pta
ke v
alu
e; T
BR
, ta
rget to
backgro
un
d r
atio.
*Pu
blic
ation d
ate
15
Tabl
e 2
– C
linic
al stu
die
s o
f aort
ic v
alv
e s
ten
osis
and 1
8F
-NaF
Stud
y/A
utho
rs
Year
* Si
te
Des
ign/
Stud
y Ty
pe
Incl
usio
n C
riter
ia
Patie
nt
Num
ber
Dos
e (M
Bq)
U
ptak
e Pe
riod
(min
)
Aim
Pr
imar
y O
utco
me
Mea
sure
/Pre
vale
nce
(Pat
ient
s)
Res
ults
Hya
fil e
t al.2
6 201
2
Aort
ic
valv
e
Retr
osp
ective
S
evere
AV
S p
atie
nts
and
pa
tien
ts f
ree o
f aort
ic v
alv
ula
r calc
ium
on C
T,
with
18F
-Na
F P
ET
/CT
fo
r oncolo
gic
or
rhe
um
ato
logic
purp
oses
15
4/k
g o
f bod
y
weig
ht
40
18F
-Na
F a
ccum
ula
tio
n in
deg
en
era
tive
ao
rtic
valv
es
Hig
he
r T
BR
valu
es th
an
th
e c
on
trol gro
up/1
00%
w
ith s
eve
re A
VS
; 0%
fre
e
of valv
ula
r calc
ium
18F
-Na
F a
ccum
ula
ted
in c
alc
ifie
d v
alv
es. A
ll patients
with k
no
wn A
VS
ha
d inte
nse 1
8F
-NaF
accum
ula
tio
n o
n p
revio
us P
ET
/CT
. P
atients
fr
ee o
f valv
e c
alc
ium
had n
o s
ignific
ant
18F
-Na
F
accum
ula
tio
n.
Dw
eck
et a
l.27
201
2
Aort
ic
valv
e
Pro
sp
ective
C
ontr
ol subje
cts
an
d
patients
ag
ed
>50
ye
ars
with a
ort
ic
scle
rosis
and
mild
, m
odera
te a
nd
seve
re A
VS
121
124±
10
66±7
18F
-Na
F a
nd 1
8F
-FD
G
upta
ke c
om
pa
riso
n in
diffe
rent sta
ges o
f a
ort
ic
ste
nosis
TB
Rm
ax >
1.9
7 (
hig
he
r contr
ol gro
up v
alu
e)/
0%
contr
ol patients
, 4
5%
with
aort
ic s
cle
rosis
and
91%
w
ith A
VS
(76%
mild
; 9
5%
m
odera
te; 1
00%
severe
)
18F
-Na
F u
pta
ke h
ighe
r in
pa
tien
ts w
ith a
ort
ic
scle
rosis
and
ste
no
sis
. 18F
-Na
F a
ctivity
incre
ased w
ith d
ise
ase s
everity
. A
ll m
easure
s
of
18F
-Na
F u
pta
ke c
orr
ela
ted
with in
cre
asin
g
aort
ic jet
velo
city,
valv
e c
alc
ium
score
and
oth
er
ech
oca
rdio
gra
phic
me
asu
res o
f A
VS
seve
rity
.
Dw
eck
et a
l.28
201
3
Aort
ic
valv
e,
coro
na
ry
art
erie
s,
tho
racic
aort
a
and
bon
e
Pro
sp
ective
P
atien
ts a
ge
d >
50
ye
ars
with a
ort
ic
scle
rosis
and
mild
, m
odera
te a
nd
seve
re A
VS
101
125±
10
66±6
18F
-Na
F a
nd 1
8F
-FD
G
upta
ke c
om
pa
riso
n in
aort
ic v
alv
e c
alc
ific
atio
n
with t
hat m
easure
d in
ath
ero
scle
rosis
an
d b
on
e
Incre
ased 1
8F
-NaF
activity
com
pa
red
with
backgro
un
d/1
00%
Weak/a
bsent
co
rrela
tions b
etw
een c
alc
ium
score
s a
nd
calc
ific
ath
ero
ma
, as b
etw
een
calc
ium
score
s a
nd
bo
ne
min
era
l d
en
sity.
Valv
ula
r 18F
-Na
F a
ctivity h
ighe
r th
an in t
he
aort
a a
nd c
orr
ela
ted
str
ongly
with A
VS
seve
rity
. N
o c
linic
ally
sig
nific
ant corr
ela
tions
with b
loo
d m
ark
ers
of
calc
ium
meta
bolis
m.
Dw
eck
et a
l.29
201
4
Aort
ic
valv
e
Pro
sp
ective
A
VS
30
120
-126
60
18F
-Na
F a
nd 1
8F
-FD
G
upta
ke c
om
pa
riso
n w
ith
aort
ic v
alv
e h
isto
logic
al
chara
cte
rizatio
n a
nd
pre
dic
tion o
f dis
ea
se
pro
gre
ssio
n
TB
Rm
ax>
1.9
7/1
00%
18F
-Na
F u
pta
ke c
orr
ela
ted w
ith h
isto
log
ical
mark
ers
of active c
alc
ific
atio
n (
TN
AP
and
oste
ocalc
in)
an
d w
as a
good
pro
gre
ssio
n
pre
dic
tor
in v
alv
e C
T c
alc
ium
score
s a
t 1 y
ear.
18F
-NaF
, fluori
ne
-18
sodiu
m flu
orid
e;
18F
-FD
G, flu
orin
e-1
8 f
luoro
-deoxy-g
lucose;
AV
S, a
ort
ic v
alv
e s
ten
osis
; C
T, com
pute
d tom
ogra
ph
y;
PE
T, positro
n
em
issio
n tom
ogra
ph
y;
TB
R, ta
rget
to b
ackgro
und r
atio;
TN
AP
, tissue
no
nspecific
alk
alin
e p
hosp
hata
se.
*Pu
blic
ation d
ate
16
DISCUSSION
By targeting active microcalcification areas, 18F-NaF PET has enhanced the study of
CVD, with potential staging of different lesion types and assessment of disease progression.
In this systematic review we aimed to resume the emerging data related to the use of
18F-NaF in CV fields. There is an association between 18F-NaF uptake and CV risk factors
and also with high-risk patients. Such findings suggest that measurements of this tracer’s
accumulation are associated to plaque instability and AVS disease progression. The
integration of overall risk assessment with lesion characteristics, by non-invasive molecular
imaging, may be valuable and allow further insights into accurate individual risk prediction,
along with tailored primary/secondary CVD prevention interventions (antiplatelets, high
intensity lipid lowering therapies, etc.).
18F-NaF proved to be of value to the identification of plaque characteristics, but we
have yet to clarify the clinical potential of this analysis. Are we really identifying the unstable
plaque, the holy grail of preventive cardiology? Despite major advances in atheroma fine
characterization, from different invasive intravascular imaging modalities and coronary CT,
the medical community gradually lost some enthusiasm in the appealing concept of
vulnerable plaque. In fact, even though the evidence from PROSPECT demonstrated that
some plaque characteristics increase the probability of event, it is still more likely to have
complications in other territories, due to a higher plaque number.36 Over time, the focus
shifted to the “vulnerable patient” thesis, with a comprehensive analysis of several risk
factors in order to address overall CVD prevention.37 Indeed, the multivariable analysis of a
recent large study showed that the higher risk of CV events conferred by the presence of
both obstructive disease and adverse plaque features was not independent from coronary
calcium score (CCS).38 When compared to CCS, carotid arteries ultrasound or risk
estimation employing clinical calculators, 18F-NaF molecular imaging has the potential to non-
invasively identify high-risk plaques in several vascular territories, conveying anatomical and
metabolic data, thus entailing a broader measure of CV risk stratification. However, this
hypothesis requires testing in large longitudinal studies.
AVS is the most common valvular disease in developed countries, with rising
prevalence in parallel with ageing. Its progression is not yet completely understood and
therapeutic/preventive measures still remain a challenge with underlying scarce disease-
modifying results. Initial data shows that 18F-NaF may predict disease activity and
progression, thus being a valuable tool both to the assessment of AVS and the
documentation of novel therapies’ effect, without the need for extensive follow-up periods
with contemporary imaging techniques.
17
The emerging data on 18F-NaF imaging has several limitations. Many studies used
small sample size with limited external validity, such as oncological populations.
Furthermore, there is no agreement in scanning methodology with inhomogeneous
measures and cut-off criteria (“significant/positive uptake” classification). PET/CT limitations
in spatial resolution can hamper the visualization of small vessels and the patient’s radiation
exposure is not negligible. For the latter, newer machines with magnetic resonance can
lower the radiation dose.
In conclusion, there is mounting evidence on the utility of 18F-NaF PET imaging to
identify atheroma instability and CVD progression. Future potential uses of this technology
include CV risk stratification, selection of patients eligible to intensive CV prevention
strategies, identification of culprit plaques in multivessel disease, or even to serve as a
surrogate endpoint for CVD trials. However, further prospective clinical studies are necessary
to better define the role of 18F-NaF uptake, standardization of the imaging acquisition
methodology and measurement tools.
NEW KNOWLEDGE GAINED
There is growing evidence on 18F-NaF PET molecular imaging potentialities, namely
in the identification of high-risk atheroma plaque, high-risk CV patients and aortic stenosis
progression. Microcalcification identification is an emergent field in the study of CVD.
AGRADECIMENTOS
À Professora Doutora Maria João Vidigal Ferreira, orientadora desta tese, por toda a
confiança depositada em mim e neste trabalho e por todo o apoio na sua concretização.
Ao Dr. Manuel Oliveira-Santos, co-orientador desta tese, pela partilha dos
conhecimentos na área de Cardiologia e pelo contributo para o desenvolvimento e correção
do texto.
Ao Professor Doutor Lino Gonçalves por permitir e incentivar a realização de projetos
de trabalho como este no seu serviço.
À Professora Doutora Helena Donato, pela revisão metodológica deste trabalho.
18
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22
APPENDIX I – Results of search strategy diagram
18F-NaF, sodium fluoride; AAA, abdominal aortic aneurysm; AVS, aortic valve stenosis.
Records screened (n = 67)
Records excluded: Not clinical trials or/and not correlated 18F-NaF
with the atherosclerosis, AVS or AAA
(n = 352)
Full-text articles assessed for eligibility
(n = 30)
Studies included in final review
(n = 31)
Records excluded: Not full articles
(n = 37)
Records after duplicate removal (n = 419)
Records identified through database searching
(n = 449)
Record included: Other applications
(Takayasu Arteritis) (n = 1)