Core Facilities:
CAIN is founded on a number of Cores, each of which will serve the entire network by
acting as a focus of excellence in one particular area of imaging or clinical research
expertise. Extensive has been made of already established provincial and national
resources, such as CFI-funded infrastructure. Data harvesting includes comprehensive
vessel and end organ imaging; circulating blood markers; biomaterial for genetic
screening; and pathological analysis in those cases yielding tissue. Relevant clinical data
is being obtained from patients at baseline when entering the program and during
follow-up; follow-up outcome information will also exploit national database registries.
Imaging techniques that allow characterization of the vessel wall in both coronary and
carotid artery settings that are already in the clinical domain or are close to clinical prime
time are being used. In the coronary circulation, intravascular ultrasound (IVUS) is
already an accepted imaging technique that allows the interrogation of the coronary
vessel. A new but rapidly emerging technique that also provides vessel wall
and lumen data is multidetector coronary CT angiography. In the carotid arteries,
ultrasound has been a mainstay of imaging, but Canadian advances in 3-dimensional
carotid ultrasound have taken this to a new level. More recently MRI has been applied to
the investigation of carotid vessel wall disease. In order to assess end organ damage, MRI
is also being used to assess myocardial necrosis and function in the heart and evidence of
cerebral ischaemia and fiber tract disruption in the brain. Core sites with expertise in
image acquisition and data analysis are the central resources for the dissemination of
expertise within the network and handling of multiparametric data from the two tissue
beds. Once the patient is recruited to the network, the opportunity exists to obtain
detailed relevant clinical information, blood for circulating biomarkers related to
atherosclerotic disease as well as for genetic profiling.
Current Research Projects:
The current research activities are organized around three fundamental research themes.
Theme 1: vascular biology of atherosclerotic plaque; Theme 2: vascular imaging
technology development and assessment; and Theme 3: clinical translation and practice.
Theme 1: Vascular biology of atherosclerotic plaque. Research projects within this
theme are addressing fundamental questions around the behaviour of atheromatous
plaque. These questions are directed in both horizontal and longitudinal dimensions,
dissecting information regarding unique features of plaque components and their
behaviour over time. The natural history of the plaque is viewed from three time points:
plaque initiation; plaque progression and triggering of plaque complication. The
network allows investigation of these time points addressing questions focusing on the
genetics of atheroma; the role of stimuli such as diabetes and hyperlipidaemia; disease
processes within the plaque, including inflammation, neovascularisation and
haemorrhage; and the role of hypertension, haemodynamics and the interaction with the
blood constituents at acute plaque rupture.
Project 1: Magnetic resonance imaging characterization of carotid plaque and
prediction of end-organ and clinical outcomes.
The primary outcome of this study is to accurately characterise carotid plaque
morphology in non-surgical patients with mild to moderate (50-70%) carotid disease.
We will also assess evidence of ischaemic brain disease. Imaging will be at baseline
and thereafter at one and two years or sooner if presenting clinically in order to
monitor the natural history of carotid atherosclerosis and its effect on end-organ brain
disease. Patients with previously detected carotid stenosis between 50-70% not
undergoing carotid endarterectomy will be eligible for this trial. Because this
population is heterogeneous, it will be subdivided into symptomatic (<6 months) and
asymptomatic but high-risk vasculopaths (disease in another vascular bed; diabetic;
hypercholesterol). Patients will undergo MRI scanning of the brain and carotid.
Patients will consent to baseline scanning and follow up at 1 and 2 years, and
databasing of clinical and imaging data. After each imaging session images will be
processed, stored locally and also sent to a central repository. Patients at any time re-
presenting with clinical signs or symptoms will undergo re scanning as per protocol.
500 patients will be recruited over a 2 year period in anticipation of study completion
within 4 years.
Project 1 Executive Committee members include:
Alan Moody (chair)
Brian Rutt
Richard Frayne
Sandra Black
Eric Larose
Christian Bocti
Josie Pressacco
Theme 2: Vascular imaging technology development and assessment. Research projects
within this theme will entail the validation of developing technologies through
quantitative histological examination of surgical specimens. The imaging techniques
including coronary IVUS, 3D carotid ultrasound, MRI and CT, have specifically been
chosen as they are already in, or close to, clinical or clinical trial usage and are broadly
available in Canada, and therefore knowledge gained as a result of CAIN studies will be
rapidly translated into clinical practice. Important gaps still exist, however, in knowing
how these imaging technologies should be optimized for atherosclerosis imaging in the
two vascular territories of interest, and in generating rigorous evidence regarding most-
appropriate imaging technologies/combinations and algorithms with respect to clinical
accuracy, clinical utility and cost effectiveness within the medical system. Research
projects in this theme will focus on these gaps, and will exploit the depth of our network
in all relevant imaging technologies as well as the breadth of expertise that will be
available to investigators through our core facilities, not only in the areas of imaging
technologies but also in the cross-disciplinary expertise spanning the areas of image and
data analysis, tissue banking and analysis, clinical trials, outcomes and population
research.
Project 2: Imaging vulnerable plaque: Histological validation
In this study, 150 patients scheduled for carotid endarterectomy will undergo
preoperative imaging with 3-D ultrasound, PET/CT, and in a subset of patients
(approximately 2/3 of cases) also 3 Tesla MRI with gadolinium contrast, and
ultrasound bubble studies to assess vascularity of plaques. 3-D ultrasound features of
vulnerable plaque will include ulceration, plaque surface roughness, plaque volume
and plaque composition assessed both by gray scale and plaque texture analysis;
PET-CT will use fluorodeoxyglucose to assess plaque inflammation; MRI plaque
composition will assess lipid core, cap thickness and intraplaque hemorrhage. All
these features will be validated by 3-D histology on endarterectomy specimens
removed en bloc.
Project 2 Executive Committee members include:
David Spence (chair)
Alan Moody
Sandra Black
Rob Beanlands
J-C Tardif
Martin Jaffe
Rob deKemp
Stephanie Wilson
Theme 3: Clinical translation and practice. While the pathobiological research interest
of CAIN centers around atherosclerosis, the clinical burden generated by atherosclerotic
disease, is always within the end organ supplied by the affected vessel. The network has
therefore been structured to address this fundamental association using advancing
imaging technologies and informatics. Research projects within this theme correlate
atherosclerotic disease phenotypes, as defined by the imaging methods and algorithms
developed through Themes 1 and 2, with end-organ damage (eg. cardiac failure, brain
ischemia, vascular dementia, as defined by imaging metrics) and clinical outcomes (eg.
myocardial infarction, stroke, death). This research theme therefore interacts with the
other two in order to develop 1) improved understanding of the underlying vascular
mechanisms resulting in the above end organ conditions; 2) improved and validated
imaging techniques/algorithms that will allow improved detection of vulnerable patients;
and 3) application of this knowledge in therapeutic trials to reduce cardiovascular and
neurovascular morbidity and mortality.
Project 3: Correlation between coronary and carotid atherosclerosis disease
and links with clinical outcomes
This is a prospective, multi-center imaging study expecting to enroll
approximately 2000 patients scheduled for clinically-indicated coronary
angiography. Following written informed consent these subjects will undergo a
coronary intravascular ultrasound (IVUS) examination and a carotid ultrasound
examination (the latter allowing measurements of the intimal-medial thickness
and 3-D ultrasound assessment of carotid plaque burden and carotid vessel
dimensions). Following a 24-month follow-up period, patients will then undergo
repeat coronary intravascular ultrasonography and standard invasive coronary
angiography as well as carotid ultrasound examination. Patients will also be
contacted by phone on an annual basis for the collection of major cardiovascular
events (5 years total). Correlations for atherosclerosis burden between the carotid
and coronary vascular beds, between rates of progression in the beds, and,
between imaging parameters and cardiovascular events will be evaluated. A
substudy to evaluate carotid MRI and CT angiography will also be included.
Project 3 Executive Committee members include:
J-C Tardif (chair)
David Spence
Ben Chow
Philippe L’Allier
Rob Beanlands
Lawrence Title
Matthias Friedrich
Josep Rodes
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Projects