Dynamic Contrast-Enhanced MRI to Study Atherosclerotic Plaque Microvasculature
Curr Atheroscler Rep
Dynamic Contrast-Enhanced MRI to Study Atherosclerotic Plaque Microvasculature
Raf H. M. van Hoof 0 1 2
Sylvia Heeneman 0 1 2
Joachim E. Wildberger 0 1 2
M. Eline Kooi 0 1 2
M. Eline Kooi 0 1 2
0 Department of Pathology, Maastricht University Medical Center (MUMC) , P.O. Box 5800, Maastricht 6202 AZ , The Netherlands
1 CARIM School for Cardiovascular Diseases, Maastricht University , P.O. Box 616, Maastricht 6200 MD , The Netherlands
2 Sylvia Heeneman
Rupture of a vulnerable atherosclerotic plaque of the carotid artery is an important underlying cause of clinical ischemic events, such as stroke. Abundant microvasculature has been identified as an important aspect contributing to plaque vulnerability. Plaque microvasculature can be studied non-invasively with dynamic contrast-enhanced (DCE-)MRI in animals and patients. In recent years, several DCE-MRI studies have been published evaluating the association between microvasculature and other key features of plaque vulnerability (e.g., inflammation and intraplaque hemorrhage), as well as the effects of novel therapeutic interventions. The present paper reviews this literature, focusing on DCE-MRI methods of acquisition and analysis of atherosclerotic plaques, the current state and future potential of DCE-MRI in the evaluation of plaque microvasculature in clinical and preclinical settings.
Atherosclerosis; Dynamic contrast-enhanced MRI; Microvasculature; Quantification
Published online: 26 April 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
Department of Radiology, Maastricht University Medical Center
(MUMC), P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
Rupture of a vulnerable atherosclerotic plaque is an important
underlying cause of clinical ischemic events, such as stroke [
Therefore, visualization of vulnerable plaques may aid in the
identification of patients who have an increased risk for a
clinical event. Inflammatory cells play an important role during the
development and progression of atherosclerosis [
atherosclerotic plaques, activated macrophages have a high
metabolic rate, inducing hypoxia which stimulates the
formation of new microvessels originating from the outer layer of the
vessel wall, the adventitia [
]. These newly formed
microvessels generally have impaired endothelial integrity,
which can lead to extravasation of inflammatory cells and
erythrocytes from the microvessel lumen into plaque tissue
. Extravasation of erythrocytes is generally considered as
an important contributing factor to intraplaque hemorrhage
]. Because lipids constitute 40 % of the erythrocyte
], extravasation of erythrocytes leads to increased
cholesterol deposition in the plaque tissue, which in turn
stimulates further recruitment of inflammatory cells. All the above
biological events, especially leaky plaque microvasculature,
are considered key features in plaque destabilization [
The microvasculature in plaques are very small (up to
∼100 μm in diameter) but can be studied non-invasively by
several imaging modalities, including contrast-enhanced
ultrasound (CEUS) [
], positron emission tomography
], and dynamic contrast-enhanced magnetic
resonance imaging (DCE-MRI) . MRI is a well-established
imaging modality that can be used to visualize the main
plaque components: areas of IPH, the lipid-rich necrotic core,
and fibrous cap status [
]. Early studies developed MRI
for the detection of morphological and chemical components
by studying specimen from surgery (carotid endarterectomy
(CEA)). These ex vivo specimens were advantageous for
testing and developing MRI sequences, but the lack of blood
precludes studying of the dynamics from DCE [
In recent years, a number of studies have applied
DCEMRI to study atherosclerotic plaque microvasculature. The
present paper reviews the current state and future potential
of DCE-MRI in the evaluation of plaque microvasculature
with applications in animals and patients. First, because the
methods of DCE-MRI are now well-developed and widely
applied but are not familiar to a general audience, we begin
with principles and acquisition methods of DCE-MRI and
methods for (semi)quantitative analysis of DCE-MRI data.
Second, an overview is given of publications on DCE-MRI
of plaque microvasculature (Table 1) used to study one of the
following aspects: (1) associations between plaque
microvasculature and other plaque features, (2) longitudinal changes in
plaque microvasculature, (3) comparison of different animal
groups and human subjects with a different cardiovascular risk
profile, and (4) evaluation of therapy response. Finally, future
challenges and potential for DCE-MRI to study plaque
microvasculature will be discussed.
DCE-MRI Methods to Study Plaque
Principles of DCE-MRI
All DCE-MRI experiments require serial acquisition of MR
images acquired in a brief time interval to study
atherosclerotic plaque microvasculature (Fig. 1). After acquisition of
anatomical references (Fig. 1a), the first images of the series,
acquired before contrast injection, are used to determine
baseline signal intensity of the atherosclerotic plaque tissue. Bolus
injection of a low molecular weight non-specific
Gadoliniumbased contrast medium follows, and image acquisition is
continued for several minutes. During this period, the bolus of
contrast medium will be distributed, resulting in signal
enhancement of the blood vessel lumen, vessel wall due to
leakage of the contrast medium through damaged endothelial, and
other tissues, such as skeletal muscle (Fig. 1b). In this image,
the vessel lumen (circle) appears bright. A ring of
enhancement in the outer (adventitial layer) part of the vessel wall
(indicated by white arrows) can be clearly observed. The
signal enhancement in the vessel wall depends on flow,
microvascular density, the ability of the contrast medium to leak
from the microvasculature into the extravascular extracellular
space, and reflux. After analysis of the DCE-MR images,
parametric maps (Fig. 1c) of the resulting parameter can be
generated, indicating local leaky plaque microvasculature. In
DCE-MRI studies of atherosclerosis to date, linear or cyclic
Gadolinium-based contrast media have been used.
DCE-MRI studies of brain and tumor perfusion mostly use a
contrast medium injection rate of 2 ml/s (typically 0.1 mmol/
kg). Such fast injection rates result in quick passage of the bolus
through the vessel and a high-contrast medium peak
concentration, necessitating a higher temporal resolution for MR
acquisition and compromising spatial resolution. For the evaluation
of carotid atherosclerosis using DCE-MRI, however, high
spatial resolution is required for accurate visualization of the vessel
wall. Therefore, some DCE-MRI studies [
] have used a
slower injection rate of 0.5 ml/s in plaque imaging. Previous
research has shown that a high injection rate is most beneficial
for high Ktrans values (>0.2 min−1) . Typically, within the
atherosclerotic lesion, mean Ktrans values below 0.15 are
], and therefore, a lower injection rate may be applied.
Signal enhancement-time curves of DCE-MR images can
be analyzed voxelwise or using a region-of-interest.
Especially in the voxelwise analysis, movement of the subject
during acquisition of the different DCE-MRI sequence time
frames may pose a problem. A solution is to manually shift
individual time frames to correctly align the images, or
alternatively, to use post-processing methods for automated
movement correction and noise reduction [
Pulse Sequences for DCE-MRI of Plaque
Currently, two main categories of pulse sequences for
DCEMRI of atherosclerotic plaque microvasculature are
employed: Bbright blood^ or Bblack blood^. Black blood
imaging facilitates improved delineation of the inner vessel wall,
whereas bright blood imaging enables to determine the CM
concentration in the vessel lumen for each patient individually.
Because the luminal CM concentration cannot be quantified
accurately, quantitative analysis of black blood DCE-MRI
with pharmacokinetic models can only be performed using a
reference region model [
] or previously determined
generalized input functions [
]. Recently, dedicated imaging
methods have been proposed combining bright and black
blood images in an interleaved fashion, allowing improved
delineation of the vessel wall from black blood images as well
as extraction of vascular input function based on lumen signal
intensity from bright blood images [
A compromise between the desired spatial and the required
temporal resolution must be made regardless of the imaging
method used. Current studies (both in rabbits and patients)
employed an in-plane spatial acquisition resolution of
approximately 0.5 × 0.5 mm2. The preclinical rabbit studies have
employed a temporal resolution of 5 s for 2D acquisition
techniques and lower temporal resolution (30 s) for 3D techniques.
In patient studies, the temporal resolution ranges from 15 to
30 s per time frame.
Table 1 Overview of DCE-MRI studies of atherosclerotic plaque
microvasculature. Overview of studies investigating the atherosclerotic
plaque microvasculature using dynamic contrast-enhanced MRI: subjects
(human or rabbits), analysis method (quantitative or semi-quantitative),
main study purpose, and study outcome are shown
DCE-MRI (AUC) showed a trend towards a
decreased microvasculature after treatment
Ktrans and vp (Patlak) differed significantly
between plaque components (lipid core,
IPH, calcifications, loose matrix, and
fibrous tissue), except between
calcifications and IPH.
Weak, inverse relationship between
inflammation (18F-FDG PET-CT, mean
TBR) and plaque perfusion (DCE-MRI,
Ktrans (extended TK))
Intensive lipid therapy (using atorvastatin,
niacin, and colesevelam) results in a
reduction in Ktrans (Patlak) after one year
The Patlak model is the most suited
quantitative model for description of
carotid plaque microvasculature
Strong correlation (ρ = 0.80, p < 0.001)
between DCE-MRI and histological
measured fractional vascular areas
Ktrans (Patlak) is a quantitative and non
invasive marker of plaque inflammation
(ρ = 0.75, p < 0.001) and microvasculature
(ρ = 0.71, p < 0.001)
Adventitial Ktrans (Patlak) was significantly
correlated with the amount of
microvasculature (ρ = 0.41, p = 0.04) and
macrophages (ρ = 0.49, p = 0.01)
High exposure to particle matter may be
associated with plaque neovascularization,
measured with DCE-MRI (AUC)
Shorter duration of statin therapy before
occurrence of clinical event is associated
with increased vp (Patlak)
Presence of IPH was associated with an
increase of 28 % of adventitial Ktrans
Weak, positive relationship between
inflammation (18F-FDG PET-CT, TBR)
and plaque perfusion (DCE-MRI, Ktrans
Correlation between 18F-FDG PET (TBR)
and DCE-MRI (Ktrans, Patlak) measurements
varied with clinical conditions
DCE-MRI dynamic contrast-enhanced MRI, 18 F-FDG 18 fluorine-fluorodeoxyglucose, PET-CT positron emission tomography/computed tomography,
AUC area under the curve, NIRF near-infrared fluorescence, CVD cardiovascular disease, CEA carotid endarterectomy, CHD coronary heart disease,
TBR target-to-background ratio, NZW New Zealand White
a Atherosclerosis was induced by a balloon injury of the aorta in combination with a high cholesterol-enriched diet (1.0 %)
b Pharmacologic triggering was performed to stimulate plaque disruption
c Atherosclerosis was induced by a balloon injury of the aorta in combination with a low cholesterol enriched diet (<1.0 %) combined with palm oil
d Atherosclerosis was induced by a balloon injury of the aorta in combination with a low cholesterol enriched diet (<1.0 %)
vessel wall (indicated by white arrows), which is attributed to the
microvasculature originating from the adventitia. Finally, in c, a parametric
Ktrans map is overlaid on DCE-MRI image shown in b. In this parametric
map, voxel wise determined Ktrans values are color encoded from 0 to
0.2 min−1. Within this overlay, the lipid-rich necrotic core in the center of
the plaque, exhibits low Ktrans values (dark), while the highly
vascularized adventitia (high Ktrans values) at the outer rim (indicated
by the arrows) is clearly visualized (red regions). Circle, internal carotid
artery; star, external carotid artery; diamond, sternocleidoid muscle.
Figure adapted from Truijman et al. [
Semi-Quantitative Assessment of the Microvasculature
Validation of Semi-Quantitative DCE-MRI Parameters
The microvasculature can be assessed semi-quantitatively
using the area-under-the-curve (AUC) of the (relative) signal
enhancement curve. This requires that start- and end-time
points are selected over which the AUC will be calculated.
Generally, the moment of contrast arrival in the tissue of
interest is chosen as the starting point, and the end time point is
chosen empirically. It must be noted that when the end point is
chosen relatively close to the contrast injection, the AUC
reflects early contrast arrival, whereas a later end point will
cause the AUC to reflect total leakage (and entrapment) of
contrast medium in the plaque tissue.
The main advantage of semi-quantitative analyses is the
relatively easy implementation. However, the information is
limited because there is no direct relationship between the
AUC and (patho)physiological parameters. Although research
in the field of oncology [
] has shown that the AUC reflects
pathophysiology, it does so non-specifically, meaning that one
particular AUC value can indicate a number of biological
properties. Thus, an increased AUC can indicate increased leakage
of the contrast medium from the microvasculature, increased
density of microvessels, increased flow through the
microvasculature, a decrease in reflux from the extracellular
extravascular space to the microvasculature, or a combination of these.
Therefore, changes or differences in the AUC may result from a
variety of phenomena so that it may be difficult to attribute
these changes to a single, underlying physiological cause.
Similarly, effects of therapeutic interventions may potentially
be obscured using the AUC. Another drawback of
semiquantitative analysis is the difficulty of direct comparison of
results between studies because the AUC also depend on
settings of the MR system, such as receiver gain.
Validation of semi-quantitative DCE-MRI was performed
in several balloon injured cholesterol-fed New Zealand
White rabbit studies. It was found that the AUC positively
correlated with microvessel count in the intima of
histological specimens (Pearson’s ρ of 0.89 (p = 0.016) and
0.91 (p = 0.011) for the AUC 2 and 7 min after contrast
injection, respectively) [
]. Furthermore, later research
] showed a good interscan and excellent intra- and
inter-observer reproducibility (all ICCs > 0.75, p < 0.01).
Another atherosclerotic rabbit study compared two
three-dimensional (3D) high spatial resolution DCE-MRI
sequences (3D turbo field echo (TFE) with
motionsensitized-driven equilibrium (MSDE) preparation and a
3D turbo spin echo (TSE) sequence) [
]. A moderate
Pearson correlation was found between AUC and ex vivo
permeability measur ements using E vans Blue (an
albumin-binding dye used for quantification of ex vivo
vascular permeability) near-infrared fluorescence (NIRF)
(ρ = 0.45 for 3D TFE MRI and ρ = 0.39 for 3D TSE MRI).
In addition, a fourfold improvement of temporal
resolution was achieved when using compressed sensing by
retrospective undersampling and reconstruction. In another
study, comparison between in vivo (3D DCE-MRI) and
ex vivo (Cy7-labeled near-infrared fluorescence [NIRF])
measures of microvascular permeability in the aortic wall
of atherosclerotic rabbits showed a high degree of
correlation between both imaging modalities (r2 = 0.65,
p < 0.0001) [
These studies [
27, 29, 30 , 32
] have demonstrated
reproducible representation of plaque microvasculature through
semi-quantitative DCE-MRI parameters.
Quantitative Assessment of the Microvasculature
Pharmacokinetic modeling allows the quantification of
contrast medium distribution over a tissue of interest with the
main advantage of deriving parameters of the in vivo physical
quantities of the amount, flow, and leakiness of the
A number of quantitative DCE-MRI data analysis models
have been applied in the evaluation of atherosclerotic plaque
microvasculature (Table 2). These models describe the
relationship between the concentration of the (extracellular)
contrast medium in the blood plasma (Cp) and the extracellular
extravascular space (Ce) according to the two-compartment
model and using the parameters Ktrans, ve, and vp. Ktrans, the
transfer constant of contrast medium from plasma to the tissue
compartment, serves as an indicator of blood supply and
vessel permeability within the atherosclerotic tissue. The
parameters ve and vp represent the extravascular extracellular space
and the plasma fractional volume, respectively. A schematic
representation of the physiological meaning of the parameters
is shown in Fig. 2.
The modified/extended Tofts and Kermode (TK) model
] is a commonly employed analytical solution for the
two-compartment model [
], estimating all three
pharmacokinetic parameters (Ktrans, ve, and vp). The original TK
model, which was proposed for the study of multiple sclerosis
], does not take vascular contribution into account (i.e., vp
is assumed to be negligible). The Patlak model [
that reflux, i.e., transfer of contrast medium from the tissue
Table 2 Overview of quantitative DCE-MRI models used in the
analysis of atherosclerosis. Quantitative pharmacokinetic models used for the
analysis of atherosclerosis based on the two-compartment model. The
modified/extended Tofts and Kermode model is the analytical solution
compartment back to the blood plasma (Ktrans/ve), is
negligible. Recently, an approximation of the modified TK model has
been introduced as an intermediate solution between the
modified TK and the Patlak model: the extended graphical model
]. This model uses the first-order term of a Taylor series
from the modified TK model to estimate ve.
Vascular Input Function
One essential requirement for quantitative analysis of
DCEMRI data is knowledge of the contrast medium concentration
in the blood vessel over time, commonly, referred to as the
arterial or vascular input function (AIF/VIF). Two main
features of the VIF are a high relative peak concentration and a
short bolus passage compared to other tissues. Accurate
determination of the VIF requires a relatively high temporal
resolution, which usually results in compromise with regard to the
spatial resolution that can be achieved.
Two strategies can be employed for the determination of
VIF. The first strategy is based on the assumption that VIF is
similar in all subjects and a generalized population-averaged
VIF, obtained from literature or determined in a cohort is used
24, 39, 46, 50
]. An advantage of this method is that data
acquisition and analysis requirements are simplified .
The second strategy involves measurement of
patientspecific function, giving the potential advantage of accounting
for variations between subjects [
]. Previous research in
oncology found comparable results using either method, and the
use of population-averaged vascular input functions resulted
in increased [
] or comparable [
] reproducibility. In
clinical studies of atherosclerotic plaque microvasculature, a
for the two-compartment model. The extended graphical model is based
on a second order Taylor expansion of the modified/extended Tofts and
Modified/extended Tofts and Kermode (TK)
Tofts and Kermode
Extended Graphical Model
dt ¼ Ve CpðtÞ−CeðtÞ
CtðtÞ ¼ vpCpðtÞ þ veCeðtÞ
CtðtÞ ¼ vpCpðtÞ þ Ktrans∫ CpðtÞe−Ktvraensðt−τÞdτ
CtðtÞ ¼ Ktrans∫ CpðtÞe−Ktvraensðt−τÞdτ
CtðtÞ ¼ vpCpðtÞ þ Ktrans∫ CpðtÞdτ
CtðtÞ ¼ vpCpðtÞ þ Ktrans∫ CpðtÞdτ−
Ktrans2 t τ1
ve ∫0 ∫0 Cpðτ2Þdτ2dτ1
Fig. 2 Schematic representation of parameters used in pharmacokinetic
models for analysis of atherosclerotic plaque microvasculature. Within a
single region of interest or voxel, the fractional blood volume
(microvasculature) is represented by vp, while the fraction of the
extracellular extravascular space is represented by ve. Contrast medium
transfer rate from the microvasculature to the extracellular extravascular space
is given by Ktrans; the reflux is described by Ktrans/ve. In most DCE-MRI
studies, an extracellular contrast medium with a low molecular weight is
used. For quantitative data analysis, therefore, a two-compartment model
can be used (i.e., vascular and extracellular extravascular compartments).
Based on this general concept and setting various assumptions, several
different quantitative models can be derived. An overview of these
models is presented in Table 2
generalized VIF is the most commonly chosen method,
probably because of the required spatial resolution for accurate
imaging of atherosclerotic plaque in the carotid artery. The
generalized VIF can be obtained from a separate study cohort
where acquisition is performed with a higher temporal
resolution and a lower spatial resolution.
The VIF with MRI can be calculated by two different
methods. The first method uses the magnitude of the
acquired MR signal and is based on conversion of the relative
signal enhancement to contrast medium concentration
using the Ernst equation [
]. For this conversion, blood
relaxation and contrast medium relaxivity rates are taken
into account. A second method based on MR signal phase
has been developed more recently [
]. First used in
brain perfusion studies with dynamic susceptibility MRI
, the technique is increasingly used in DCE-MRI [
]. Efforts have been made to compare the
magnitudeand phase-based techniques [
24, 59, 65–67
], showing a
strong potential for the phase-based technique, allowing
accurate VIF quantification. In a DCE-MRI study of 17
symptomatic patients with a mild to severe carotid
stenosis, it was found that the magnitude-based VIF resulted in a
strong underestimation of lumen contrast medium
concent r a t i o n as co m p a r e d to t h e p h a s e - b a s ed VI F [ 2 4] .
Simulations and phantom experiments showed that this
underestimation is caused by local blood flow velocity,
which leads to saturation of the magnitude MR signal
caused by the shortened T1 relaxation time in the presence
of contrast medium. Analysis of Ktrans values using
population-averaged input functions showed a strong
positive correlation between the two methods, although
absolute values significantly differed.
Validation of Quantitative DCE-MRI Parameters
Histological validation of carotid plaque DCE-MRI has been
carried out using reference specimens from patients after
carotid endarterectomy (CEA). However, the drawback of all
such validation studies is that these are performed in patients
scheduled for CEA. Large randomized trials have shown that
symptomatic patients with severe ipsilateral stenosis benefit
the most from CEA [
]. This population is more likely to
have developed advanced atherosclerotic plaques. In addition,
the surgeon removes the intima and part of the media of the
vessel wall and the adventitia, from which microvasculature
], is missing in the CEA specimen. An additional
limitation of the comparison of in vivo MRI with histological
measurements as a reference standard is the comparison of a
thin histological slice to thicker MR imaging slice (typically
2 mm). Due to the heterogeneous nature of atherosclerotic
lesions, this may result in partial volume effects.
Despite these drawbacks, a strong and positive correlation
between fractional blood volume derived from in vivo MRI
and post-surgical histology (0.80, p < 0.001) was found in 16
CEA patients [
]. In addition, a significant Pearson
correlation was reported between the transfer constants Ktrans
calculated from in vivo DCE-MRI with postsurgical histologic
measurements of the microvessel area (ρ = 0.71, p < 0.001
for the entire vessel wall Ktrans and ρ = 0.41, p < 0.04 for
adventitial Ktrans). Additionally, an association between Ktrans
and other postsurgical histological parameters was reported,
i.e., macrophage density (ρ = 0.75, p < 0.001 for the vessel
wall Ktrans and ρ = 0.49, p < 0.01 for adventitial Ktrans), loose
matrix area (ρ = 0.50, p = 0.01, for vessel wall Ktrans) [
It was also shown that Ktrans and vp differed significantly
between different plaque components (lipid core, IPH,
calcifications, loose matrix, and fibrous tissue), except between
calcifications and IPH .
Reproducibility, fit error, parameter uncertainty, and
correlation with histology of carotid plaque DCE-MRI were
compared for four pharmacokinetic models in patients with mild to
severe carotid stenosis [
]. Analysis of 43 patients showed
the highest relative fit error for the Tofts model, while the
other three models did not differ in this regard. The Patlak
model had a significant lower parameter uncertainty for
Ktrans as compared to the other models. Reproducibility was
studied in 16 asymptomatic patients with 30–69 % carotid
stenosis who underwent imaging twice with several (4.3
± 2.8) days between the two examinations. Results showed a
good reproducibility for all considered pharmacokinetic
models (ICC > 0.6, p < 0.05) for Ktrans and significant
scanrescan ICCs for ve (Tofts) and vp (Patlak). Correlation with
histologic findings in 13 CEA patients showed significant
positive Pearson’s correlation (ρ = 0.7; p < 0.01) with the entire
vessel wall microvasculature for all models, with the
exception of the Tofts model. It was concluded that the Patlak model
was the most suited of these four models for pharmacokinetic
modeling of the microvasculature in atherosclerotic plaques
]. Another study [
], however, found favorable results for
the extended graphical model for simulated and selected in
vivo data of carotid plaques with good to excellent image
quality. Their results showed that a compromise between
noise and bias sensitivity has to be made when choosing
between the Patlak and extended graphical models.
The scan-rescan reproducibility of DCE-MRI was also
investigated in a multi-center study [
] of 35 subjects
with established cardiovascular disease recruited from 15
hospitals. Results showed a moderate reproducibility for
Ktrans with a coefficient of variation of 25 %. The
relatively high dropout rate within the study (31.4 %)
suggested a need for intensive operator training, an optimized
imaging protocol, and quality control.
The dependence of model parameters on contrast medium
was investigated in a study comparing two extracellular
contrast media [
]. Quantitative analysis of DCE-MR images
demonstrated a lower Ktrans when using gadobenate
dimeglumine (0.0846 min−1) as compared to gadodiamide
(0.101 min−1, p < 0.01), while no difference in vp was found.
In order to facilitate direct comparison of quantitative
DCEMRI parameters between- or in longitudinal studies, the use of
the same contrast medium is recommended.
Taken together, despite the recognized limitations, the
above studies demonstrate the suitability of quantitative
DCE-MRI parameters for reproducibly determining plaque
Overview of DCE MRI Studies to Study Plaque
Association Between DCE-MRI Parameters and Other
Many plaque characteristics and pathological features
contribute to the risk for disruption and thrombosis, and studies have
been designed to investigate possible associations between
plaque microvasculature and other plaque features. In recent
years, several studies [
31, 37, 45 , 46, 47
] were carried out to
investigate associations between DCE-MRI parameters,
plaque inflammation, and the presence of IPH. In a preclinical
study of cholesterol-fed balloon-injured atherosclerotic rabbits
], a positive Pearson correlation (ρ = 0.70, p = 0.01) was
found between DCE-MRI derived parameters and
histologically determined plaque macrophage content.
The relationship between DCE-MRI parameters and plaque
inflammation using 18fluorine-fluorodeoxyglucose (18F-FDG)
PET-computed tomography (CT) has been investigated in
several clinical studies [
37, 46, 47
]. One study of 49 symptomatic
patients with mild to moderate carotid stenosis [
] reported a
weak positive correlation (Spearman ρ = 0.30, p = 0.035)
between plaque inflammation (mean Target-to-Background Ratio
(TBR) on 18F-FDG PET-CT) and plaque perfusion (mean
Ktrans). Another study of 33 patients [
] with coronary heart
disease (CHD) or CHD risk equivalent and a carotid plaque with
TBR ≥ 1.6 on 18F-FDG PET-CT [
] found a significant inverse
relationship between plaque perfusion (Ktrans) and plaque
inflammation on 18F-FDG PET-CT of ρ = -0.24 (p < 0.05). A
subsequent study of 41 patients with carotid plaque [
] found that
correlations depend on the clinical condition of patients. Overall,
a weak, marginal non-significant correlation (Spearman ρ = 0.22,
p = 0.068) was found for all, both symptomatic and
asymptomatic, carotid plaques. A significant difference in Spearman
correlation coefficients between TBR and Ktrans was found when
grouped according to the symptomatic and asymptomatic
carotid plaques (p = 0.033): a significant correlation (Spearman
ρ = 0.59, p = 0.006) was found for symptomatic carotid plaques,
not seen for asymptomatic plaques (Spearman ρ = 0.07,
p = 0.625). Also, an inverse relationship was found between
the time since the last neurological event and both parameters
(Spearman ρ = −0.94 for TBR and Spearman ρ = −0.69 for
Ktrans). These results point towards a complex interplay between
inflammation and microvasculature in atherosclerotic plaques
that is difficult to capture in clinical imaging.
The link between plaque microvasculature and the specific
feature of intraplaque hemorrhage (IPH) has been investigated
in symptomatic patients with moderate to severe carotid
]. The presence of IPH on MP-RAGE MR images
was associated with a significant increase in Ktrans of 28 %
(p < 0.001) in the adventitial layer of the vessel wall as
compared to arteries where IPH was absent (p < 0.001). A
multivariate analysis adjusting for symptomatic status, degree of
stenosis, and male sex showed that the increased Ktrans in
arteries with IPH remained significant (p = 0.018).
These studies show the potential of DCE-MRI as a tool to
gain more insight in relation between plaque microvasculature
and other features of vulnerable atherosclerotic lesions.
Monitoring Longitudinal Changes in Plaque
DCE-MRI can be used to follow progression of
atherosclerotic plaques, as illustrated by a preclinical study [
cholesterol-fed atherosclerotic rabbits. One group of rabbits
was imaged 3 months after balloon denudation, immediately
followed by euthanasia, and a second group at 3 and 6 months
after balloon denudation. From 3 to 6 months after balloon
denudation, an increase of 40 % in Ktrans was found measured
by DCE-MRI, suggesting that DCE-MRI can be used to
investigate plaque microvasculature development.
Differences Between Different Animal Groups
and Human Subjects with a Different Cardiovascular
In a recent rabbit study [
], investigating the development of a
microfluidic chip for potential future nanomedicines an
increased AUC within the abdominal aorta for atherosclerotic
animals as compared to control animals was reported. In
another study of cholesterol-fed rabbits with induced plaque
], it was shown that ruptured plaques can be
distinguished from stable plaques by spatial-temporal texture-based
features of DCE-MRI. The effect of exposure to high
particulate airborne matter on atherosclerosis was investigated in
BGround Zero^ workers in New York City with high and low
exposure to particulate matter using DCE-MRI [
with high exposure had a significantly higher AUC in the
carotid artery (+41 %) as compared to subjects with low exposure
(p = 0.016), indicating increased changes of the plaque
microvasculature. These changes may range from increased leakage
of contrast medium from the microvasculature, increased
microvessel density, increased flow through the
microvasculature, decreased reflux from the extracellular extravascular space
to the microvasculature, or a combination. The authors of the
study concluded that a high exposure to particulate matter may
lead to increased plaque microvasculature, potentially
indicating an increased risk for further development of atherosclerosis.
Evaluation of Therapies
DCE-MRI enables the study of plaque microvasculature
changes over time, making it useful in animal and patient drug effect
studies. Changes in microvasculature may reflect changes in
phenotype and/or vulnerability of the atherosclerotic plaque.
DCE-MRI has been employed in several preclinical
cholesterol-fed balloon-injured atherosclerotic rabbit studies
investigating potential anti-inflammatory treatments of
]. The effect of liposome-encapsulated
prednisolone phosphate (L-PLP) on atherosclerosis was
investigated using MR imaging before treatment, immediately after
injection with L-PLP, and over time [
]. A reduction of the
plaque AUC was found from pre-treatment to 2 days
posttreatment, revealing early changes in microvascular
permeability after treatment. In a further study, the
antiinflammatory effects of pioglitazone on atherosclerotic
plaques were investigated [
]. DCE-MRI analysis showed
a 22 % decrease in AUC for the treatment group (p < 0.01)
over the study time period of 3 months, while no decrease in
plaque enhancement was found for the control group. No
changes in vessel wall area measurements were found during
the study period for either animal group. A third study [
evaluated the anti-inflammatory effects of a liver X receptor
(LXR) agonist which induces reversal cholesterol transport, as
compared to atorvastatin. The 3-month treatment with LXR
did not lead to changes of the microvasculature, whereas
treatment with atorvastatin caused a trend towards a decrease in
microvasculature (p = 0.06). No differences in vessel wall area
measurements were found. Combined, these studies have
shown the potential of DCE-MRI to study changes of the
plaque microvasculature in the evaluation of potential new
therapies. A limitation of these studies, however, is that the
rabbits did not exhibit plaque disruption with luminal
thrombosis, the clinical endpoint of high risk plaques.
DCE-MRI has been used to study the effect of intensive
lipid therapy over a period of 12 months [
] in patients with
coronary artery disease or carotid disease and increased levels
(≥120 mg/dl) of apolipoprotein B from the Carotid Plaque
Composition study [
]. Results of the study show that
12month therapy leads to a significant reduction of 21 % in
Ktrans. This is consistent with the hypothesis that intensive lipid
therapy results in a reduction of the extent and permeability of
atherosclerotic plaque microvasculature. A study with 98
subjects with established cardiovascular disease [
from the AIM-HIGH trial [
] found an inverse association
between vp (plaque microvasculature fraction) and the duration
of statin therapy. Statins are commonly used to lower lipid
levels and also possess anti-inflammatory properties [
These results suggest that a relationship exists between duration
of statin therapy and plaque microvasculature, which could
reflect a decreased level of vascular inflammation.
The above studies on DCE-MRI of plaque
microvasculature have measured differences between treatment groups or
subjects with increased cardiovascular risk and shown that
DCE-MRI can be employed effectively as an evaluation tool.
Challenges and Future Perspectives in DCE-MRI of Atherosclerosis
To further advance DCE-MRI for wider use in clinical
practice, uniform acquisition and analysis methods need to be
agreed upon. Previous studies have shown that
DCE-MRIderived parameters are influenced by the contrast medium,
vascular input function, and which pharmacokinetic model
is used, making direct cross-study comparisons difficult. Use
of a standard imaging and data analysis protocol is essential,
therefore, for longitudinal studies of plaque microvasculature.
A very important clinical precaution is use of a stable
Gadolinium-based contrast medium [
] using low dosages
to minimize the risks for nephrogenic systemic fibrosis and
deposition of the contrast medium in the brain.
The recent introduction of interleaved acquisition methods
], providing both bright and black blood images, may be
an important step toward the determination of an
individualized vascular input function. In addition, 3D acquisition
] may provide increased spatial accuracy as
compared to currently employed 2D techniques, although at the
expense of temporal resolution. Currently, these 3D
acquisition techniques have only been explored in preclinical rabbit
studies; their potential in clinical studies remains to be
All clinical DCE-MRI studies, to date, have been
performed at 1.5 and 3.0 T. The potential of carotid MRI at
7.0 T has already been explored [
], and results show a
potential increase in signal-to-noise ratio (SNR) due to the
increased field strength. However, the increase in SNR may
be diminished by increased relaxivity of the contrast medium,
which may also require longer scan times. The potentially
increased SNR at 7.0 T would allow increased spatial and/or
temporal resolution, but these studies also demonstrate that
further technical developments are required to enable
complete plaque characterization.
A s s o c i a t i o n s b et w e e n p l a q u e m i c r o v a s c u l a t u r e
(measured using DCE-MRI) and plaque inflammation
(measured by 18F-FDG uptake or macrophage content)
remain an important area to be studied further since
varying results have been reported to date. The reported
association between and plaque microvasculature and
intraplaque hemorrhage could be studied longitudinally.
The recent introduction of hybrid PET-MRI systems
provides excellent opportunities for further investigation
of the relationships between these processes using a
single imaging system. Recent research [
already shown the potential of hybrid PET-MR systems
for the imaging of atherosclerosis. However, the
additional value of DCE-MRI in PET/MR imaging is yet to
The predictive value of DCE-MRI for plaque progression
or development of vulnerable plaque features is of great
interest and remains to be determined; in addition, its predictive
value for cerebrovascular ischemic events needs to be
investigated in a prospective clinical trial.
Applications of DCE-MRI can be extended beyond the
carotid artery to other (human) vascular territories, such as
the microvasculature in the aortic wall of abdominal aortic
]. These measurements were reproducible
with a high technical success rate, and the Patlak model was
the most suited pharmacokinetic model. Future studies are
warranted to investigate the predictive potential of
DCE-MRI derived parameters for abdominal aortic
aneurysm rupture risk.
inflammation and intraplaque hemorrhage, for assessing
effectiveness of therapeutic interventions, and in the
evaluation of plaque microvasculature changes over time
and between groups with increased cardiovascular risks.
Future studies could apply DCE-MRI to elucidate
plaque development mechanisms, specifically the
interplay between inflammation, increased microvasculature,
and intraplaque hemorrhage. Also of great interest is the
potential predictive value of plaque microvasculature
DCE-MRI for plaque progression and future
cerebrovascular ischemic events (such as stroke).
The studies discussed in the present review have been
identified through a database search in MEDLINE in December
2 0 1 5 u s i n g t h e f o l l o w i n g s e a r c h t e r m s : Bc a r o t i d
Batherosclerotic plaques^/Bplaque^ AND Bhuman^/Brabbit^
AND BDCE-MRI^/Bdynamic contrast enhanced MRI^/
BMRI^/Bdynamic contrast enhanced magnetic resonance
imaging^/Bmagnetic resonance imaging^ AND Bneovessels^/
Bmicrovasculature^/Binflammation^. Resulting abstracts and
articles were screened and references checked for possible
Acknowledgments This research was performed within the framework
of CTMM, the Center for Translational Molecular Medicine (www.ctmm.
nl), project PARISk (grant 01C-202), and supported by the Dutch Heart
Foundation. M.E. Kooi is supported by Aspasia Grant 015.008.047 from
the Netherlands Organization for Scientific Research. J.E. Wildberger and
M.E. Kooi are supported by Stichting de Weijerhorst. The authors would
like to thank Estelle C. Nijssen for critically reviewing the manuscript.
Compliance with Ethical Standards
Conflict of Interest Raf H.M. van Hoof declares grant support from
CTMM. Sylvia Heeneman declares no conflict of interest. Joachim E.
Wildberger declares grant support from Siemens, Philips, Bayer, and
AGFA, and declares personal fees from Siemens and Bayer. M. Eline
Kooi declares grant support from CTMM, Stichting de Weijerhorst,
NWO (Aspasia), and Servier.
Human and Animal Rights and Informed Consent All studies by
R.H.M. van Hoof, S. Heeneman, J.E. Wildberger, and M.E. Kooi
involving animal and/or human subjects were performed after approval by the
appropriate institutional review boards. Where required, written informed
consent was obtained from all participants.
Over the past decade, DCE-MRI has developed from a novel
imaging tool to a useful non-invasive research tool used in
animal and patient studies of plaque microvasculature.
DCEMRI has been used to investigate the relationship between
plaque microvasculature and other plaque features such as
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