Imaging inflammation in atherosclerotic plaques: Just make it easy!
Imaging inflammation in atherosclerotic plaques: Just make it easy!
Fabien Hyafil 0 1
Jonathan Vigne 0
PharmD 0 1
0 Reprint requests: Fabien Hyafil , MD, PhD , Department of Nuclear Medicine, Centre Hospitalier Universitaire Bichat, Assistance Publique - Hoˆpitaux de Paris, De ́partement Hospitalo-Universitaire FIRE, Inserm 1148, Universite ́ Paris Diderot , 46 rue Henri Huchard, 75018 Paris , France
1 Department of Nuclear Medicine, Centre Hospitalier Universitaire Bichat, Assistance Publique - Hoˆpitaux de Paris, De ́partement Hospitalo-Universitaire FIRE, Inserm 1148, Universite ́ Paris Diderot , Paris , France
The presence of inflammatory cells is a hallmark of unstable atherosclerotic plaques. Several imaging approaches have been developed for the noninvasive detection of inflammatory activities in atherosclerotic plaques. Positron emission tomography (PET) imaging with the injection of 18F-fluorodeoxyglucose (FDG) is currently the most widely used imaging technique to evaluate the density of activated macrophages in atherosclerotic plaques. Nevertheless, FDGPET imaging has logistical and technical constraints that represent an important obstacle to the wider use of this approach for the evaluation of patients with atherosclerosis. In a similar way as in the oncological field, the balance between the benefits and costs of new drugs need to be improved in patients with cardiovascular diseases. PET imaging of plaque inflammation might represent a very useful tool to identify patients who could benefit the most from anti-inflammatory treatments and to exclude patients with other causes of inflammation who are the most likely to develop severe side effects under these drugs. The availability of radiotracers targeting more specifically inflammation in atherosclerotic plaques would greatly facilitate the logistic organization of this imaging and help to expand the use of PET for the evaluation of atherosclerotic patients.
Atherosclerosis Æ PET Æ molecular imaging Æ vascular imaging Æ inflammation Æ molecular imaging agents
ROLE OF INFLAMMATION IN PLAQUE
The presence of inflammatory cells is a hallmark of unstable atherosclerotic plaques. Ruptured atherosclerotic plaques contain higher densities of macrophages
and lymphocytes1 than plaques from patients with
stable coronary artery disease (CAD). Macrophages
play a key role in plaque destabilization: they release
locally pro-inflammatory cytokines and secrete enzymes
capable of directly digesting the fibrous cap of the
plaque. Where the degree of inflammation is sufficient,
the fibrous cap can rupture, exposing the thrombogenic
lipid core to the bloodstream. This may cause local
arterial thrombosis and result in clinical events such as
myocardial infarction or ischemic stroke. The infiltration
of atherosclerotic plaques by inflammatory cells is not
limited to the culprit lesion in patients dying from acute
coronary syndromes, but has also been observed in all
atherosclerotic plaques present along the coronary
arterial beds in favor of a diffuse inflammatory process in
the vessel wall of symptomatic patients.2 The intensity
of inflammation in atherosclerotic plaques can be
approached by measuring the level of high-sensitivity
C reactive protein (hs-CRP) in blood. Elevated levels of
hs-CRP have been associated with an increased risk of
cardiovascular events independent of the cholesterol
level.3,4 A limitation of hs-CRP is its lack of specificity
for inflammation in atherosclerotic plaques. In
particular, myocardial or cerebral necrosis following plaque
rupture and arterial thrombosis can cause an increase in
CRP values that limits its value for grading the intensity
of plaque inflammation in patients with acute ischemic
complications of atherosclerosis. Based on the results of
observational studies showing the increased risk of
patients with stable atherosclerosis and high hs-CRP
values, interventional clinical studies have been set up to
evaluate whether anti-inflammatory drugs might be
effective to prevent cardiovascular events. The
Canakinumab Antiinflammatory Thrombosis Outcome Study
(CANTOS) study5 has tested the efficacy of
canakinumab, an inhibitor of interleukin-1b, in 10 000 patients
with coronary heart disease and hs-CRP [ 2 mg/L. At
4 years, a small decrease in the rate of cardiovascular
events was evidenced in patients treated with the
inhibitor of interleukin-1b, but at the expense of an
increased incidence of severe infections. The results of
the CANTOS study underscore the need for specific
biomarkers of vascular inflammation to identify
atherosclerotic patients who might benefit the most
from anti-inflammatory treatments.
IMAGING INFLAMMATION WITH PET
In the past 20 years, several imaging technologies
have been developed for the noninvasive detection of
inflammatory activities in atherosclerotic plaques.6
Positron emission tomography (PET) imaging with the
injection of 18F-fluorodeoxyglucose (FDG) is currently
the most widely used imaging technique to evaluate the
density of activated macrophages in atherosclerotic
plaques. FDG is avidly taken up by activated hypoxic
macrophages and its uptake in vessel wall correlated
closely with the density of macrophages determined
histologically both in animal models of atherosclerosis
and in patients with carotid disease.7,8 Nevertheless,
FDG-PET imaging has logistical and technical
constraints that represent an important obstacle to a wider
use of this approach for the evaluation of patients with
atherosclerosis. For FDG-PET acquisition, patients need
to fast at least 6 h before the imaging to limit FDG
uptake in peripheral muscle and maintain blood glucose
in normal ranges. In addition, myocardial FDG uptake
should be suppressed for the analysis of coronary
arteries by extending the fasting period to 12 h and
asking patients to start a low-carb high-fat diet 24 h
before PET acquisition.9 In carotid arteries, the analysis
of the vascular signal can be hampered by the high FDG
uptake in structures in close vicinity to the vessels such
as lymph nodes or cervical muscles. Radiotracers that
target more specifically inflammatory cells in the vessel
wall would greatly facilitate the noninvasive evaluation
of atherosclerosis with PET.
RADIOTRACERS ALTERNATIVE TO FDG
FOR THE DETECTION OF INFLAMMATION
IN ATHEROSCLEROTIC PLAQUES
In this issue of the Journal of Nuclear Cardiology,
Meester EJ et al.10 have tested the tracer
DOTAbutylamino-NorBIRT (DANBIRT) labeled with
111Indium in a mice model of atherosclerosis.
DANBIRT binds to Leukocyte Function-associated Antigen-1
(LFA-1) expressed on leukocytes and might thus
represent an interesting candidate tracer for the more specific
identification on inflammatory activities in
atherosclerotic plaques. The long half-life of 111Indium associated
to its low SPECT signal and high radiation burden
represent an important limitation of this approach.
Nevertheless, 111Indium can be replaced by 68Gallium
in the DOTA cycle resulting in a PET radiotracer that
might have favorable properties for atherosclerosis
imaging. DANBIRT would then extend the list of
radiotracers that target receptors expressed on
inflammatory cells in atherosclerotic plaques, which already
include the somatostatin receptor SST2,11 the
translocator protein TSPO,12 the mannose receptor,13
CXCR4,14 the folate15 and interleukin receptors, 16 and
the choline transporter.17 One might wonder why none
of these radiotracers has managed until now to
effectively replace FDG for the evaluation of inflammation in
atherosclerotic plaques. In fact, one of the challenges in
detecting inflammation in plaque is that this activity is
concentrated in a relatively small area of the vascular
wall, the region surrounding the lipid core including the
fibrous cap with some signal also extending in the
adjacent adventitia, in contrast to active vasculitis in
which a large number of inflammatory cells infiltrate the
entire vascular wall. FDG presents the advantage of
providing a strong signal on PET thanks to its high
accumulation in metabolically active cells and to the
expression of GLUT receptors on a large variety of
inflammatory cells, including activated macrophages
and lymphocytes. Novel radiotracers have been
developed as alternative to FDG to detect specifically
activated macrophages. The challenge for these
radiotracers is to target a molecule or biological activity that
is sufficiently expressed in atherosclerotic plaques to be
detectable on PET, and also to demonstrate that this
target is clinically relevant for the evaluation of
atherosclerosis in patients, i.e., an increase in the PET
signal is associated with the progression of
atherosclerosis and the risk of cardiovascular events. In addition to
scientific aspects, the business model to bring on the
market a radiotracer dedicated only to atherosclerosis
imaging is currently complex and risky for
radiopharmaceutical companies. A more realistic approach is thus
to develop radiotracers targeting inflammatory cells with
clinical applications in other pathologies than
atherosclerosis, or to identify radiotracers targeting
receptors expressed on tumor cells that are also present
on activated macrophages. Using the latter strategy, two
PET radiotracers, 68Ga-DOTATATE and
68Ga-pentixafor, have recently been found to accumulate in
atherosclerotic plaques and to bind, respectively, to the
SSTR2 and CXCR4 receptors expressed on activated
macrophages. Tarkin et al.18 tested 68Ga-DOTATATE
for the detection of inflammation in atherosclerotic
plaques. They found in patients imaged sequentially
with FDG and 68Ga-DOTATATE a good correlation
between the intensity of the signal measured in coronary
and carotid atherosclerotic plaques between the two
radiotracers, and improved image quality with
68GaDOTATATE thanks to less background signal in
structures adjacent to plaques in comparison to FDG. PET
radiotracers targeting SST2 present the advantage that
they have already approved for the evaluation of patients
with neuro-endocrine tumors. This should greatly
facilitate the evaluation of these radiotracers for the detection
of inflammation in atherosclerotic plaques.
In the last years, major developments in
noninvasive imaging technologies of the vessels have allowed us
to move from a view centered on the degree of luminal
stenosis to a broader vision showing the variety and
complexity of atherosclerotic plaques that develop in the
vessel wall over time. Patients with similar degrees of
luminal stenosis can have very different plaque aspects.
Several morphological and molecular imaging
biomarkers of high-risk atherosclerotic plaques have been
identified and associated to an increased risk of
cardiovascular events. In a similar way as in the oncological
field, the balance between the benefits and costs of new
drugs need to be improved in patients with
cardiovascular diseases. Nevertheless, information on plaque
composition provided by imaging is rarely used for the
selection of patients for treatments. PET imaging of
plaque inflammation might represent a very useful tool
to identify patients who could benefit the most from
anti-inflammatory treatments and to exclude patients
with other causes of inflammation who are the most
likely to develop severe side effects under these drugs.
The availability of radiotracers targeting more
specifically inflammation in atherosclerotic plaques would
greatly simplify the logistic organization for this
imaging approach and could help to expand the use of
PET for the evaluation of atherosclerotic patients.
F Hyafil and J. Vigne have nothing to disclose in relation
to this Editorial.
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