Prevalence of vulnerable plaque in type 2 Diabetes Mellitus and its predictive value for future ischemic strokes

More than 240 000 people have suffered from a stroke in the Netherlands. One
third of the strokes causes sudden death and another third of the patients
remains permanently disabled. A stroke frequently occurs unannounced, e.g.
without any previous neurological symptoms. The presence of a carotid plaque
accounts for 15-20% of ischemic strokes. A large multi-centre randomised
surgery trial has shown that asymptomatic individuals younger than 75 years of
age with 60-90% carotid stenosis benefit from carotid endarterectomy, although
the benefit of surgery is only marginal. Therefore, in the Netherlands, these
individuals are generally not operated on. However, still 13.4% of these
individualswill suffer from a stroke within 10 years. Therefore, it would be
highly beneficial if there would be better measures to identify indviduals with
increased stroke risk, beyond the degree of stenosis. It is well known that
rupture of a vulnerable plaque is an important underlying cause of stroke.
Recently, it was demonstrated in several studies that MRI is able to identify
carotid plaque vulnerability, and that intraplaque haemorrhage as detected with
MRI can predict a stroke. In parallel, it is also well known that type 2
Diabetes Mellitus is a strong risk factor for stroke. However, little is known
about the prevalence of vulnerable plaques in individuals with type 2 Diabetes
Mellitus, impaired glucose or normal glucose tolerance, its relation with
(silent) brain infarcts, and its associated risk for future stroke.

Primary:
2. To investigate the prevalence of vulnerable plaques, i.e. plaques with
intraplaque hemorrhage on MRI, in individuals with type 2 diabetes, impaired
and normal glucose tolerance and a minimal plaque thickness of 2mm on
ultrasonography. To determine the predictive value of intraplaque hemorrhage
for future ischemic stroke in individuals with and without type 2 diabetes
mellitus.
Secondary:
2e. To determine the predictive value of plaque features, i.e. intraplaque
hemorrhage, plaque volume, normalized wall index and volume of calcifications
as identified with carotid MRI for future cardiovascular disease.
2f. To relate the presence of intraplaque hemorrhage and other plaque features,
i.e. plaque volume, normalized wall index and volume of calcifications with
the presence of (silent) brain infarcts on brain MRI in type 2 diabetes,
impaired and normal glucose tolerance.
2g. To compare plaque features of plaques, i.e. intraplaque hemorrhage, plaque
volume, normalized wall index and volume of calcificationsfrom asymptomatic
individuals with plaques from symptomatic patients (on the symptomatic and
asymptomatic side). Note that symptomatic patients are currently being enrolled
in another ongoing study within the azM (the PARISk study; METC 09-2-082 14).
2h. To study the inter-scanner reproducibility of the 3.0 Tesla MRI protocol in
a small subgroup.

The present study is a prospective cohort MRI study on 1680 individuals with
type 2 diabetes, impaired glucose tolerance or normal glucose tolerance.
Participants will be recruited from DMS and followed for an average duration of
10 years, to determine the predictive value of carotid plaque features for
ischemic stroke and cardiovascular disease (objective 1 and 2a). Ischemic
strokes due to carotid stenosis is defined as an ischemic stroke and a
significant (>50%) stenosis or occlusion at the carotid territory and no
cardiac source of emboli. Cardiovascular disease is defined as the total of
coronary heart disease, heart failure and stroke.
Recruitment
Subjects will be approached by an investigator after the carotid ultrasound
scan as assessed by DMS. The plaque in the carotid artery should have a wall
thickness of at least 2 mm determined from the ultrasound scan performed by
DMS. The minimal wall thickness of 2 mm was chosen based on the following
considerations:
* it is expected that the majority (95%) of individuals that will experience an
ischemic stroke, due to carotid stenosis, during ten years of follow-up, have a
wall thickness of >2mm at baseline
* a carotid wall of 2 mm is of sufficient thickness taking into account the
resolution of the MRI scans, and
* as atherosclerosis is a progressive disease it is expected that the carotid
plaque is at least of similar size (* 2mm) than during the ultrasound scan by
DMS.

MRI protocol
All subjects will undergo the MR imaging on a 3.0 Tesla unit. First, the
carotid bifurcation will be identified by means of MR angiography without
contrast material enhancement. Subsequently, transverse images will be obtained
from about 7 mm caudal to 2 cm cranial of the carotid bifurcation, so that the
complete plaque will be imaged for all individuals. Multisequence MR imaging
will be performed to assess carotid plaque features, including intraplaque
hemorrhage, plaque volume, normalized wall index and volume of calcifications,
no contrast agent will be injected. Total scan duration is approximately 40
minutes.

Future ischemic stroke and cardiovascular disease
DMS*s annual follow-up comprises of an annual follow-up questionnaire, linking
of participant data to hospital and pharmacy records and collection of
mortality data through existing up-to-date databases from Statistics
Netherlands (CBS). With the participant*s written permission (according to DMS
informed consent), we will use these data to classify the outcome measure:
ischemic stroke (objective 1) and cardiovascular disease (objective 2a).

Secondary Objectives
A cross-sectional approach will be used for objectives 2b and 2c.
On a subset of the participants, brain MRIs are performed by DMS. The brain
MRIs will be used to identify participants with (silent) brain infarct
(objective 2b).
For objective 2c, asymptomatic participants of the Type 2 Diabetes Mellitus
Plaque Study will be compared with symptomatic patients that are currently
being enrolled in an ongoing study within the azM (the PARISk study; METC
09-2-082 14).
Participants of the Type 2 Diabetes Mellitus Plaque Study are scanned on the
Siemens 3T MRI system, while in the ongoing PARISk study the scans are
performed on the Philips 3T MRI system. To analyze differences in
characteristics of asymptomatic and symptomatic plaques, it is important to
know the inter-scanner reproducibility (objective 2d). Therefore, twenty
participants will be selected for an additional scan on the Philips MRI system
within 7 days before or after the Siemens MRI scan. The scan time for the
second scan will be approximately 40min.

not applicable