Level of agreement in the assessment of carotid plaque composition between multi-contrast and multi-sequence MRI

Complications of cardiovascular disease, such as stroke, continue to be the
leading cause of death and long-term disability in the western societies.
Despite significant advances over the past 20 years in treating cardiovascular
disease, the incidence of its complications is still high and there remains an
unexpectedly high number of apparently healthy individuals who die from sudden
cardiovascular events without prior symptoms.
Stroke as a major cardiovascular complication- is in two-thirds of the cases
related to rupture of an atherosclerotic plaque, the so-called *vulnerable
plaque* of an extracranial artery (usually carotid artery). Subsequently, the
ruptured plaque develops superficial thrombosis and sheds debris into the
cerebral vasculature.

Although occasionally heralded by transient ischemic events, the majority of
strokes occur without prior prodromal symptoms. Up until now, indications for
carotid endarterectomy in have been based largely on the severity of stenosis
and symptomatology. However, the degree of luminal stenosis seems not to be the
solely factor that matters. In recent years, the plaque composition on MRI,
including intraplaque haemorrhage (IPH), a large lipid-rich necrotic core
(LRNC), and thin or ruptured fibrous cap has emerged as an important
determinant of ischemic events alongside the degree of luminal narrowing.

These characteristics of plaque vulnerability can be visualised using MRI
because of its superior soft tissue contrast. A meta-analysis by Gupta et al.
found that IPH, LRNC and thin or ruptured fibrous cap as determined by MRI,
demonstrated a hazard ratio of 4.59 (95% confidence interval (CI), 2.91-7.24),
3.00 (95% CI, 1.51-5.95), and 5.93 (95% CI, 2.65-13.20) respectively, for
future stroke or transient ischemic attack. A more recent meta-analysis by
Schindler et al. showed that the presence of IPH in carotid plaques is an
independent risk predictor for ipsilateral ischemic stroke in both symptomatic
and asymptomatic patients that is stronger than any known clinical risk
factor.

Despite the advantages of MRI in determining plaque vulnerability, it is not
yet used in daily clinical practice. One of the reasons is long MRI scan times.
To visualize different vulnerable plaque components, multiple MRI sequences
need to be acquired. This can accumulate to a scan time of around 30-40
minutes. To tackle this problem, recently multicontrast sequences have been
developed which acquire multiple contrasts in a single sequence, reducing the
total scan time significantly to less than 6 minutes. Another advantage is that
because these multiple contrasts are acquired simultaneously, they are
co-registered to each other, unlike conventional multi-sequence MRI which
acquires images with different contrasts sequentially and suffers from
misregistration errors between different contrast images.

In the present study, we will validate two multicontrast sequences namely
Multicontrast ATherosclerosis Characterization (MATCH) and Bright*blood and
black*blOOd phase SensiTive (BOOST) inversion recovery sequence. Patients with
a carotid plaque of >= 2 mm in thickness based on ultrasound or CTA will be
scanned with the two multicontrast sequences under investigation followed by
the conventional MRI sequences. Different plaque components will be delineated
independently on the conventional and on the multicontrast images by trained
observers using dedicated software to calculate the volume of the various
plaque components, the vessel wall and the lumen. In those patients that need
to undergo carotid endarterectomy in standard clinical care, the carotid
endarterectomy specimen will be collected and processed under supervision of
the pathology research laboratory. The volumetric data on plaque composition
obtained from the imaging will be compared histological quantification of
plaque composition.

The MATCH sequence acquires three different contrasts (hyper T1 weighted (T1w)
black blood, grey blood and T2 weighted (T2w) black blood). In a study with 53
patients, MATCH showed results comparable to a conventional multicontrast
protocol (Time of flight (TOF), T1w, T2w) in quantitative measures of luminal
area, outer wall area, mean area of LRNC and loose matrix, while MATCH showed a
larger mean area of IPH and calcifications. The performance of MATCH was not
compared to a hyper T1w sequence such as a three-dimensional
magnetization-prepared rapid acquisition gradient echo (MP-RAGE). MP-RAGE is
more sensitive and specific to IPH detection and the use of such a sequence
was recently recommended in a white paper with consensus recommendations by
experts [14]. In the same study , using carotid endarterectomy specimens from
13 patients as a reference, MATCH performed as well as the conventional
sequences (TOF, T1w, T2w) in detecting IPH, LRNC, loose matrix, and
calcifications with an acquisition time of only 2 * minutes. MATCH still needs
to be validated with multi-sequence MRI including a hyper T1w sequence and with
histology in larger studies.

BOOST is another multicontrast sequence initially developed for coronary plaque
imaging. The BOOST sequence to be used in the present study has been optimised
for carotid artery imaging and acquires bright and black blood images with a
single sequence. The feasibility of thrombus visualization with BOOST was shown
in an ex-vivo pig heart, but a validation study with conventional
multi-sequence MRI and histology still needs to be performed

Primary Objective:

1. The primary objective is to investigate the level of agreement between
scoring the presence of IPH on MR images acquired with MP-RAGE (conventional
sequence) with scoring IPH on the multicontrast sequences. The level of
agreement will be assessed by calculating Cohen*s kappa.


Secondary Objectives:
1. To investigate the level of agreement between scoring the presence of an
LRNC, calcifications, a thin or rupture fibrous cap, and ulcerations on the
multicontrast images versus the conventional multisequence MR images.
2. To study the correlation between the vessel wall and luminal volume and
volumes of calcifications, LRNC and IPH as delineated on the multicontrast
sequences versus the conventional multisequence MRI protocol.
3. To study the correlation between the presence/volume of calcifications,
LRNC, thin or ruptured fibrous cap, ulcerations and IPH as quantified using the
multicontrast MRI sequences and histology.

A cross-sectional validation study will be performed.

Due to the strong magnetic field and the narrow bore of an MRI scanner,
patients with contra-indications for MRI cannot be scanned. Patients with
contra-indications for MRI, such as pacemakers, vessel clips, or metal
splinters in the eye will be excluded from the study. Claustrophobic patients
are also excluded from the study. An MRI exam is safe and therefore adds no
additional risk for the patient. The patients need to invest time for the MRI
examination.

Patients with a renal clearance higher or equal to 30 ml/min/1.73 m2 will
receive a gadolinium-based contrast agent during the MRI examination. Patients
with a renal clearance of less than 30 ml/min/1.73 m2 will be scanned without
the contrast agent. The side effects of the MRI contrast agent (Gadovist) are
rare, amongst others nausea (0.25%), vomiting (0.05%), urticaria (0.04%),
feeling of warmth, tachycardia, wheals (for each 0.03%), dizziness, itching,
vasodilatation, itchy throat (for each 0.02%) and cough, dyspnoea, flushing,
hives, generalized itching, oral dryness, facial redness, sensation of heat,
skin disorder and aggravated nausea (for each, 0.01%) [3]. Out of 14299
patients, two serious adverse drug reactions (ADRs) occurred (0.01%), which
were considered by the treating physician to be probably associated with the
administration of Gadovist; one patient had a severe anaphylactic reaction and
the other presented with itching and swelling in the throat. In most cases,
side effects occur immediately after contrast injection, and therefore patients
will remain in the hospital for 30 minutes after injection. The administration
of the contrast agents is relatively safe and side effects are rare.

There are no treatment benefits to the patients; however, they will obtain the
satisfaction of advancing knowledge that may help others. If the multicontrast
sequences perform as well or better than the conventional sequences,
multicontrast sequences could replace the conventional sequences. This would
make the use of carotid plaque imaging with MRI more convenient and it will
help towards clinical translation.
MRI contrast agent and the insertion of a peripheral venous catheter are both
associated with very rare or minor adverse events.
In conclusion, the inconvenience this study will bring to included patients is
acceptable compared to the effects of the hoped diagnostic role of these
sequences in patients with carotid artery disease.