Cardiovascular disease (CVD) constitutes the greatest single serial killer in many parts of the world. According to the American Heart Association1, about 40% of deaths in the United States are due to CVD. The treatment of CVD is the most expensive item of disease categories, representing about $350 billion spent on fighting with CVD in the U.S. alone. Although the management of this insidious disease is most effective at its early stages, unfortunately there is no effective detection method available to spot such a deadly disease until plaque build-up is extremely severe and patients experience a heart attack. Drug therapy and lifestyle intervention at this stage are often found not to be very effective. It is clear that a simple, non-invasive procedure for the early detection of atherosclerotic lesions would significantly reduce the risk. While the management of CVD includes both prevention and treatment of the disease, strategies aimed at prevention are clearly more cost effective and beneficial than those that focus on treatment of advanced disease. Successful prevention depends on early assessment of individuals at a great risk. For a disease that develops over a long period of time, risk determination is difficult. Current diagnostic methods such as angiography can only detect advanced lesions, at which time expensive interventions involving surgery and hospitalization of patients are often required.
experience a heart attack. Drug therapy and lifestyle intervention at this stage are often found not to be very effective. It is clear that a simple, non-invasive procedure for the early detection of atherosclerotic lesions would significantly reduce the risk. While the management of CVD includes both prevention and treatment of the disease, strategies aimed at prevention are clearly more cost effective and beneficial than those that focus on treatment of advanced disease. Successful prevention depends on early assessment of individuals at a great risk. For a disease that develops over a long period of time, risk determination is difficult. Current diagnostic methods such as angiography can only detect advanced lesions, at which time expensive interventions involving surgery and hospitalization of patients are often required.
Several different approaches have been attempted regarding the non-invasive diagnosis of atherosclerosis. While angiography remains the standard to which many of these techniques are compared2, other methodologies include plethysmography3, Doppler and ultrasound techniques4, magnetic resonance imaging5, computed tomography6, scintigraphic detection of 111In-labeled platelets7 and 99mTc-purine8 or peptide9 analogs. Another potential approach, the focus of the following discussion, is based on the pioneering finding by Lees and colleagues that the accumulation of LDL in the arterial wall of lesioned areas (early stages of atherosclerosis) is higher than that of healthy blood vessels.10,11 Such differential accumulation of lipids is due to the elevated levels of oxidized low density lipoprotein (oxLDL) receptors (also called scavenger receptors) on the surface of lesioned cells which have a strong affinity to bind chemically modified LDLs, such as oxLDL and acetylated LDL (AcLDL). This differential uptake of LDL (by normal versus lesioned cells) provided a valid rationale for the design of a diagnostic agent for the early detection of atherosclerosis.12 In other words, compounds, if incorporated into chemically modified LDL, would be taken up by the lesioned area because of the increased levels of oxLDL receptors. In addition, if the compound incorporated into LDL is properly radiolabeled, i.e. with gamma radiation, it would permit the visualization of lesions by a gamma camera. This approach would allow the detection of atherosclerosis at a much earlier stage than by angiography, for which stenosis of the vessel would not be required for lesion detection. Early identification of the disease would allow early pharmacological and dietary interventions to prevent and/or slow down the development of atherosclerotic plaques. This detection method could also be used to monitor patients following surgical and therapeutic treatments. Furthermore, compared to angiography, which is very invasive, this radioimaging approach would be safer and also non-invasive.
Our research group has synthesized a novel cholesteral ester analog, cholesteryl 1,3-diiopanoate glyceryl ether (C2I) which was designed to be easily incorporated into AcLDL and to be resistant to hydrolysis in vivo.13,14 C2I was radiolabled with 125I and incorporated into an atherogenic carrier, AcLDL, forming a lesion-seeking agent. This lesion-seeking agent was injected into atherosclerotic animals such as high cholesterol diet-fed rabbits. After a period of time, the animals were sacrificed. Aortae of those rabbits were removed, washed and stained for histological examination, and exposed to a film to detect radioactivity. The results (see figure) showed that the distribution of radioactivity was superimposed with the plaques, indicating that C2I incorporated into LDL was selectively taken up and accumulated in the plaque regions. Similar results were also obtained in apoE/ldlr double knockout mice.14 These results suggested the potential application of C2I in detecting early stages of atherosclerosis.
The positive results so far suggest that this technology has a great potential to be further developed for human use in identifying people who are at a high risk to develop atherosclerosis. The low cost associated with this technology makes it even more suitable for mass screening. This technology may also be used as a reliable tool for pharmaceutical companies to screen potential anti-atherogenic drug candidates. This novel imaging probe may revolutionize the management of CVD. However, further studies are required with respect to this technology. For example, studies of using this technology to differentiate the vulnerable from stable plaques are important.
This research project has been funded since 1997 by several funding agencies. including Canadian Institutes of Health Research (CIHR), Canada’s Research-Based Pharmaceutical Companies (Rx&D) via its Health Research Foundation (HRF), Atlantic Canada Opportunities Agencies (ACOA), the Banting Research Foundation of Toronto, the BTG International of Philadelphia and North Atlantic Biopharma Inc. of St. John's, Canada. This technology has been granted a patent status in Canada and 13 European countries. Examinations by the U.S. and Australian patent offices should be concluded soon. Several colleagues at Memorial University of Newfoundland have contributed to the project, including Drs. Tom Scott, Lili Wang and Carl Wesolowski. Several students and research technicians have worked on the project and are greatly appreciated.
Email: hliu@mun.ca n
1. American Heart Association. 1998 Heart and Stroke Statistical Update **link-2**http:// www.amhrt.org/Scientific/HSstats98/03cardio.html**endlink**
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