A reproducibility study of novel noninvasive multimodal imaging techniques in atherosclerosis in healthy and cardiovascular diseased subjects

Atherosclerosis is the main cause of cardiovascular disease. It is a
progressive disease, characterized by the formation of plaques in the vessel
wall. After a long asymptomatic period, patients with atherosclerosis can
present with symptoms of impaired blood flow due to stenosis (e.g. stable
angina pectoris, claudicatio intermittens) or with acute complications due to
plaque rupture (e.g. myocardial infarction, ischemic stroke). Vascular imaging
techniques, like ultrasonography, magnetic resonance imaging (MRI) and
positron-emission tomography / computed tomography (PET/CT) scans, enable
detection of atherosclerosis before clinical symptoms occur. These techniques
can further be used in clinical decision making by risk stratification and as a
surrogate parameter for cardiovascular disease in therapeutic trials.

Ultrasonographic measurement of the intima-media thickness (IMT) is the most
extensively validated modality in vascular imaging. Carotid IMT can predict
future cardiovascular events and can be used as an end-point in clinical
studies evaluating cardiovascular therapy. Furthermore, stenosis grade can be
assessed by ultrasonography and is used to select patients eligible for carotid
or femoral surgery.

However, stenosis grade and IMT have shown to be insufficient, not telling the
whole story in atherosclerosis. Not only the degree of stenosis, but also the
activity and vulnerability of the plaque drive progression and complications of
atherosclerosis. Novel vascular imaging techniques, including MRI and
18-fluorodeoxyglucose (18F-FDG) PET/CT scan, do enable us to image these
important plaque characteristics.

MRI can provide high-resolution images of the carotid artery, aorta and the
femoral artery. MRI enables accurate analysis of the vessel wall dimensions and
specific structures in the atherosclerotic plaque, like lipid-rich necrotic
core, intra-plaque hemorrhage, loose matrix and the fibrous cap can be
identified. Endothelial shear stress, an important determinant in endothelial
permeability and influx of lipids and immune cells, promoting atherosclerosis,
can also be measured by MRI. Dynamic contrast enhanced MRI (DCE-MRI) makes it
possible to image vessel wall permeability, i.e. neovascularisation, in the
atherosclerotic plaque, reflecting inflammatory activity.

18fluor-fluorodeoxyglucose PET/CT (FDG-PET/CT) is a nuclear imaging technique
which measures metabolic activity by labelling glucose with a PET tracer
(18-fluor). Since atherosclerosis is now classified as an inflammatory
disease, and inflammation has high metabolic needs, FDG-PET/CT of the vessel
wall was proposed as a read-out for atherosclerotic plaque inflammation.
Indeed, FDG uptake in the vessel wall, expressed as the target (vessel wall) to
background (blood pool) ratio (TBR), is associated with the number of
macrophages in atherosclerotic lesions. and seems capable of visualizing
atherosclerotic plaque inflammation.

For implementation of vascular imaging techniques as an endpoint in clinical
translational research and clinical practise, they should be accurate and
reproducible. Reproducibility studies of MRI techniques to measure vessel wall
dimensions and wall shear stress have been performed and show good
reproducibility. However, new MRI scanners enable improved MRI techniques of
the vessel wall, including faster scans, higher spatial resolution scans and
three-dimensional MRI scans. In this study we will test the reproducibility of
these new MRI techniques to measure vessel wall dimensions and wall shear
stress.

The reproducibility of FDG-PET/CT to measure vessel wall inflammation in
patients with atherosclerotic disease was good in studies by Rudd et al. This
group is the only so far that studied the reproducibility of FDG-PET/CT. Since
FDG-PET/CT of the vessel wall is increasingly used as an endpoint in
therapeutic trials and may be implemented in clinical practise, it is important
to confirm the reproducibility of this technique by other research groups. In
the present study, we will study the reproducibility of FDG-PET/CT of the
vessel wall in subjects with cardiovascular disease and healthy volunteers. To
the best of our knowledge, there are no prior studies on this topic in healthy
volunteers.

Primary Objectives:
A. To assess the reproducibility and variability (interscan, intra- and
interreader) of novel (DCE-)MRI techniques to measure vessel wall dimensions,
wall shear stress and vessel wall permeability in healthy and cardiovascular
subjects.
B. To assess the reproducibility and variability (interscan, intra- and
interreader) of 18 F-FDG-PET/CT scan to measure vessel wall inflammation in
healthy and cardiovascular subjects.

Secondary Objective:
- To assess the correlation between the degree of arterial wall inflammation as
measured by 18F-FDG -PET/CT and wall shear stress as measured by MRI and vessel
wall permeability as measured by DCE-MRI.
- To assess the correlation between the degree of arterial wall inflammation as
assessed with 18F-FDG -PET/CT and circulating markers of inflammation.
- To assess the difference in vessel wall dimensions, wall shear stress, vessel
wall inflammation and vessel wall permeability between healthy young subjects,
healthy older subjects and cardiovascular subjects.
- To compare the reproducibility and variation of different MRI techniques to
measure vessel wall dimensions.

This study is designed as a single center, observational study. After screening
for eligibility, all subjects will undergo cardiovascular risk assessment and
laboratory testing. Thereafter, all subjects will undergo subsequently a MRI
scan and 18F-FDG -PET/CT scan.

In a subset of subjects, vascular imaging will be repeated on the same day. The
MRI scan will take 60 minutes. A repeat MRI scan of 60 minutes will be
performed after 60 minutes of rest. After the administration of 18F-FDG and a
resting period for its distribution, PET/CT scan of the carotid artery and
aorta will be performed. This scan takes 20 minutes. In subjects undergoing a
repeat 18F-FDG PET/CT scan, only the PET/CT scan will be repeated, not the
injection of 18F-FDG, thereby limiting the extra radiation exposure. This scan
again takes 20 minutes and will be performed after a resting period of 20
minutes.

The results of this study contribute to the quality of novel techniques in
atherosclerotic imaging, thereby contributing to risk stratification in
individual patients and testing of new anti-atherosclerotic treatment.
Individual subjects will gain no direct benefit from this study. The risk of
participating in this study is estimated to be low. Gadovist is routinely used
as a contrast agent in magnetic resonance imaging. Protocols that describe what
to do in case of contrast-induced hypersensitivity reactions are implemented at
our department and drugs to treat these hypersensitivity reactions are readily
available at the site of the MRI scan. MRI is a safe imaging technique without
radiation exposure. The exposure to radiation related to 18F-FDG PET/CT scan is
7.5 mSv for all subjects. This is below the maximum permitted 10 mSV per year.