Vascular Biology Imaging

The Canadian Atherosclerosis Imaging Network (CAIN) is a pan-Canadian imaging network funded through grants from the Canada Foundation for Innovation and the Canadian Institutes of Health Research. This unique research network is focused on the pathobiology of atherosclerotic disease as it pertains to the coronary and carotid circulations (Can J Cardiol. 2013 Mar;29(3):297–303).

The CAIN research program involves the creation of a unique national network focused on in vivo imaging of vessel wall disease, combined with imaging of occult end-organ disease as well as the acquisition of clinical and pathological end points. The network enables unprecedented cross-sectional and longitudinal clinical studies of patients with atherosclerotic disease in coronary or carotid vascular beds. It has been established as an international resource for studying the natural history, progression and regression of atherosclerosis, and novel therapeutic interventions aimed at treating atherosclerosis.

Vascular imaging expertise and infrastructure in all major Canadian cities are linked in this novel multidisciplinary team to form a core clinical research network. Patients are recruited from qualified sites across the country, which enables unique research into the vascular biology of atherosclerosis, imaging technology assessment and clinical vascular imaging. The project leader, co-principal investigators, core and recruitment sites are Canada’s leading atherosclerosis imaging experts.

Our understanding of the biology of vascular disease is quickly moving away from a simplistic model based on luminal stenosis. We have learned that vessels are not simple conduits. They are complex dynamic organs that have downstream effects on end-organ pathobiology. A commonly used model for the study of disease has been based on endarterectomy specimens. This approach has significantly added to our knowledge of atherosclerosis. However, histological specimens can only give a snapshot at one moment in time. Usually, a patient undergoes a surgical procedure once the extent of disease is severe; therefore, only one part of the spectrum of disease is available for analysis.

Identifying patients most at risk for atherosclerosis-related cardiovascular events (e.g., heart attacks, strokes, related death) is a challenge in research and clinical practice. Intraplaque hemorrhage (IPH), a component of unstable atherosclerotic plaque, is emerging as a marker that can identify such high-risk cardiovascular patients.

Magnetic resonance imaging can image the vessel wall with high resolution. It can also extract multiple tissue characteristics. One characteristic that is of great interest and is easily detectable by MRI is IPH. Early studies, including ours (Radiology. 2009 Aug;252(2):502–8) promisingly suggest the ability of MRI-detected IPH to identify patients at risk of heart attacks and strokes. Magnetic resonance imaging is able to reliably, rapidly and noninvasively detect IPH in routine clinical practice.

We continue to investigate MRI-detected IPH in retrospective and prospective trials to establish whether the marker improves patient outcomes.

Diabetes is a globally increasing burden that has a heavy impact on health care systems (Interact Cardiovasc Thorac Surg. 2013;16;339–46). Ever-rising prevalence rates of diabetes lead to increased vascular complications synonymous with the disease (Can J Diabetes. 2013; 37(suppl 1);S1–S212). Increased risk of cardiovascular disease and accelerated atherosclerotic development increases vulnerability of diabetic patients to their clinical endpoints (Cell Metab. 2013;17;20–33). As a result, 80% of deaths within this population are due mainly to ischemic coronary and cerebrovascular events (Statistics Canada, CANSIM Table 102-0529, 2007–2011).

Current guidelines use carotid artery stenosis to estimate atherosclerotic plaque burden and determine intervention (Stroke. 1999;30;1751–58). However, there is increasing evidence that plaque morphology plays an important role in predicting future cerebrovascular events, regardless of stenosis. Imaging and measurement of the plaque and its components have become possible, in vivo, using magnetic resonance imaging (MRI). Intraplaque hemorrhage is thought to drive atherosclerotic plaque progression, leading to plaque destabilization and disruption and resulting in ischemic strokes (Cardiovasc Imaging. 2012;5;406–8). Similarly, other plaque components, such as calcium and the lipid-rich necrotic core, are useful in staging atherosclerosis and contribute to prediction of future events.

From this database of asymptomatic, type 2 diabetic patients without evidence of carotid artery disease, we aim to identify the prevalence of complicated atherosclerotic lesions, specifically intraplaque hemorrhage within this population. These patients will have MRI and ultrasound performed at baseline and repeat imaging after one and three years. Using this, we also aim to measure plaque progression and observe the impact that the atherosclerotic plaque components may have on overall disease. The technical aspects of vessel wall measurement reproducibility and plaque component identification will also be addressed.

Flow-mediated dilation (FMD) is a macrovascular endothelium-dependent response to distal ischemia. Impaired FMD is a precursor of atherosclerosis. In those with endothelial dysfunction, FMD can be quite small. To be able to measure changes within this small dynamic range, we need to reduce the systematic error and improve accuracy.

Ultrasound and magnetic resonance imaging have been used to measure FMD noninvasively (J Cardiovas Magn Reson. 2006;8(2);381–87). Magnetic resonance imaging is less operator-dependent and less technically challenging than is ultrasound. Magnetic resonance imaging is also able to image changes in vascular cross-sectional areas. However, current MRI techniques are limited by spatial and temporal resolution. Our study aims to improve on the current MRI techniques for measuring FMD.

Intraplaque hemorrhage (IPH), a component of late-stage atherosclerosis, is a critical factor in plaque destabilization leading to stroke and myocardial infarction. Magnetic resonance imaging is able to identify IPH and allows for identification of high-risk patients. However, no routinely available tests are conducted to identify individuals at risk of IPH.

This project focuses on identifying genetic and serum biomarkers that could identify patients at risk of developing unstable vascular disease. We hypothesize that haptoglobin genotype and sCD163 levels may be important biomarkers of presence and volume of IPH that can be measured using simple blood test and genotyping methods. These rapid and cost-effective tests may help identify at-risk populations suitable for more targeted investigation.

The Canadian Alliance for Healthy Hearts and Minds is a national research study aimed at understanding better the influence of socioenvironmental and circumstantial factors on the development of cardiovascular disease (CVD). Canada’s geographic and ethnic diversity will enable researchers to examine participants of ethnic groups that are at high risk for CVD, including South Asians, East Asians, Africans and reserve-based Aboriginals. This research will assess the impact of contextual factors associated with groups ranging across the geographic and ethnic spectrums, and their relative impact compared to factors on an individual level.

Through developing a better understanding of the correlation between socioenvironmental and circumstantial factors in relation to the functioning of the cardiac and vascular system, we can improve the quality and longevity of life, and minimize the burden of cost on our health care system. The collaborative efforts of researchers, research centres and groups across Canada create a multidisciplinary team to fill existing knowledge gaps (individual risk factors in relation to social and built environments) and allow for political decisions that can minimize the CVD burden in Canada.

Vascular disease has a strong impact on quality of life and health care costs in Canada. Thus, it is important to diagnose the vascular dysfunction in early stages. The purpose of this study is to understand environmental risk factors for vascular disease, specifically carotid artery dysfunction. We aim to identify early substantial dysfunction in the carotid artery vessel using magnetic resonance imaging (MRI).

We apply in vivo high-spatial-resolution carotid 3-D MRI, using 3-D MRI of intraplaque hemorrhage and 3-D time of flight for quantification of vessel wall volume and intraplaque hemorrhage volume (MR Materials in Physics Biology and Medicine. 2004;16(5);227–34 and Int J Cardiovasc Imaging. 2013;29(7);1477–83).

Although the amount of blood vessel narrowing in the carotid and coronary arteries is a well-established risk factor for strokes and heart attacks, there remain patients with minimal to moderate narrowing who still experience ischemic events. Features and components of the atherosclerotic plaque itself provide additional information about a patient’s risk of having an ischemic event. One such feature is intraplaque hemorrhage (IPH), or bleeding within the plaque. Red blood cells that are deposited in the plaque contribute lipids and hemoglobin-derived iron, both potentially detrimental to the stability of the plaque (Eur Heart J. 2011;32:1977–85 and Arterioscler Thromb Vasc Biol. 2010;30:1347–53).

Even though statins are effective at preventing heart attacks and strokes through the reduction of cholesterol levels, there is no therapy for IPH and its proatherosclerotic effects. We have developed a preclinical model for studying the effects of IPH on atherosclerotic plaques. We have shown that IPH in this model leads to increases in markers of plaque instability. Our aim is to test whether a therapeutic agent targeted toward products of IPH will reduce their harmful effects.

Magnetic resonance images of the brain have been investigated extensively to determine whether precursors to stroke exist. Several studies show that hyperintense objects scattered throughout the white matter, known as white matter lesions (WML), are an independent risk factor for future stroke events.

To prove the relationship between WML and stroke, the volumes of WML were found by visual analysis and correlated to patient outcome. Unfortunately, obtaining volumetric measurements manually is subjective (i.e., observer-dependent), qualitative, error-prone and laborious. As a result, it is not possible to conduct large-scale research studies to understand disease on a deeper level.

Image analysis techniques combat these challenges by automatically measuring image objects in a quantitative, objective, efficient and reproducible manner. Disease can be accurately quantified for diagnostic purposes, and large patient cohorts can be analyzed efficiently for research.

In line with these goals, the focus of this research program is to design and develop image-processing methodologies that quantitatively analyze magnetic resonance images for stroke prevention by uncovering disease causes, models, trajectories and relationships. In the future, such models can be used to develop targeted, personalized therapies.