CORDA
Asymptomatic Subject Plaque Assessment Research
Contents
The CORDA mobile MR scanner will use established techniques in 200 asymptomatic subjects to image the wall of the infrarenal abdominal aorta, the wall of both carotid arteries around the bifurcation, and the lumen of the proximal right coronary artery. If atherosclerotic plaques are identified in the aorta or carotids, measurements of the plaque size and lipid content will be made. If the lumen of the aorta, carotid or coronary artery is narrowed, the velocity increase will be measured to determine stenosis severity. Plaque size, lipid content and velocity increase will be related to the presence of established risk factors. Changes in plaques and their relation to risk factors will be established with repeat imaging after 2 years. The relation of plaque characteristics to any clinical vascular events will be made over 5 years with follow-up questionnaires. This project will continue to further our understanding of how to apply MR techniques to the assessment of the vessel wall and will yield valuable research findings which will seed further projects directed at achieving CORDA’s aim of early detection and prevention of vascular disease.
MR techniques to image the arterial wall Spin-echo MRI is used to image the arterial wall as blood appears black. The vessel wall is clearly shown and atherosclerotic plaque shows as areas of wall thickening. This technique has been validated at Royal Brompton and Harefield NHS FoundationTrust with good results compared with histology in the post-mortem human aorta, and with x-ray angiography in MRI studies of plaques in the abdominal aorta. Subsequent post-mortem human, and in-vivo animal studies have shown good correlation between MR findings and gross examination and histology. Once atherosclerosis has been identified, further important plaque characteristics can be measured: The severity of stenosis relates to symptoms, the clinical need for intervention, and also prognosis,, (plaque rupture may occur because of the friction /separation losses and pressure drop associated with the increased flow velocity across the stenosis). Stenosis severity is best assessed by measuring the associated increase in blood flow velocity, and this is well validated for MR and Doppler ultrasound in carotid artery stenosis, and has been validated for MRI in-vivo in larger arteries and in-vitro for the coronaries. The lipid content of plaques is closely related to prognosis because high lipid content, (particularly beneath a thin cap) makes plaques liable to rupture precipitating clot formation, which in coronary arteries may lead to occlusion., The lipid content of relatively minor plaques may be a particularly important prognostic factor. MRI is unique in being the only non-invasive technique available which can assess plaque lipid content. This is achieved using chemical shift MR imaging.,
MR techniques to image the vessel lumen Gradient echo MRI shows blood in the arterial lumen as bright signal. This is because of rapid acquisition and compensation for the effects of flow. The vessel wall is not in general well seen, but significant stenosis of the lumen is usually identified. This has been validated in many arteries in humans by comparison with conventional x-ray angiography techniques: Examples are the aorta, carotid, renal, leg and coronary arteries. Most recently MRI of the coronary arteries has been compared with x-ray angiography, and in a selected population there was 80% concordance between the techniques for detection of stenosis.
Diaphragm monitoring (navigator echoes) Imaging of the vessel wall of many major arteries is disturbed by respiratory movement which degrades the images. Various techniques to correct for this have been attempted, but none have proved satisfactory. A new technique has now been developed which is reliable and this uses navigator echoes to monitor the diaphragm position. The images can be gated to respiratory motion, and patients may improve the acquisition by holding their breath in the correct position as shown by a light display. This MR technique is exciting because it allows elimination of most respiratory artefact in the images, which is expected to considerably improve visualisation of the arterial wall and the lumen of small arteries such as the coronaries.
Disease prevalence and interpretation of findings for the coronary arteries In-vivo coronary calcification studies suggest that the general incidence of coronary atherosclerosis in asymptomatic subjects in the 5th and 6th decades is in the order of 45% and 65% respectively, which is a similar result to that of post mortem studies of subjects dying from accidental causes (40%, 70%). In the aorta, post-mortem studies (not asymptomatic subjects or accidental death) show moderate to severe atherosclerosis of the aorta in approximately 70% of subjects in their 5th decade. It is likely therefore that plaques will be found in a significant proportion of the asymptomatic subjects in this study. Although this study will establish the ability of MR to measure lipid levels in plaques in the aorta and carotids, this is not currently possible in the coronaries where lipid related plaque rupture is particularly important, because of resolution limitations. Despite this limitation, this study will help to answer 2 important questions: Is the lipid level between plaques in different locations in an individual consistent? What is the relation of in-vivo plaque lipid content to the serum cholesterol? If this study finds that plaque lipid levels are reasonably consistent between plaques in various locations (aorta and carotid) within an individual, it may be possible to use extra-coronary plaque lipid measurements as a surrogate for coronary artery plaque lipid levels until such time that coronary artery wall imaging can be developed. There is some pathological evidence to support this possibility because aortic atherosclerosis is much more severe than expected in patients suffering myocardial infarction. In addition, the relation of plaque lipid to serum cholesterol has not been explored in-vivo before, and is particularly important in view of the success of cholesterol lowering therapies in preventing coronary events., In conclusion, the combination of a coronary luminogram and plaque lipid imaging in larger arteries may provide sufficient information to categorise patients into high and low cardiac risk on the basis of the non-invasive MR findings.
Subjects will be eligible for inclusion if they are aged 40-60 years and with no symptoms relating to the cardiovascular system. Subjects will be asked to provide the following details: Medical and drug history, age, gender, body mass index (weight/height2), and the major risk factors of family history of vascular disease, smoking history, cholesterol (total, HDL, LDL and triglycerides), and blood pressure. Subjects will be categorised into groups with 0, 1, 2, 3 or 4 major risk factors. Two hundred (200) subjects will be scanned over 2 years and approximately 40 subjects will therefore be chosen to fit into each category. Subjects will not be eligible for inclusion if any of the following are present: Pacemaker, cerebral aneurysm clips, intraocular metallic deposit, claustrophobia. As a prudent precaution only, pregnancy will be considered a reason for exclusion (but it is not a contraindication to MRI).
align="justify"Imaging Four arteries will be imaged. Transverse spin echo imaging will be performed of the infrarenal abdominal aorta to the bifurcation, and then 3cm above and below the bifurcation of both carotids. These regions are particularly prone to atherosclerosis. If plaques are identified, their size will be measured and further imaging will be performed. The lipid content will be measured with dual water/fat spin echo imaging. At the site of significant luminal narrowing, the increase in velocity at the site of the plaque will be measured by in-plane velocity mapping. For the right coronary artery, fast gradient echo imaging will be performed to image the arterial lumen. If stenosis is identified (presence of luminal signal loss), its severity will be assessed by in-plane velocity mapping. It is not anticipated that lipid imaging of coronary stenosis will be possible during this project. Diaphragm monitoring will be used to reduce respiratory artefacts.
Surface coils will be used in all cases for maximum signal. The use of phased array coils, which significantly increase signal, will be incorporated during the project.
We anticipate that imaging will last approximately 1 hour if no plaques are seen, and 90 minutes when further single plaque assessment is found to be required. If generalised disease is found involving a number of vessels then it may be necessary to ask the subject to return for completion of arterial imaging. In subjects with normal arteries, spare imaging time will be used for development of novel arterial wall imaging techniques.
We plan to rescan all subjects for follow-up, after 2 years. The risk factor profile will again be recorded. The same arterial sites will be localised accurately using the previous MR parameters and rescanned. Previously identified plaques will be remeasured, reevaluated for lipid content and if appropriate, the velocity at the plaque measured. Repeat scanning of subjects is important to understand the natural history of atherosclerosis and to determine whether progression has occurred as this is a potent predictor of future events. It will also allow an evaluation of changes in plaques in relation to risk factor profile or any changes in modifiable risk factors. Annual follow-up for a further 5 years will be by questionnaire. Although the number of vascular events may be small in this population, their occurrence will be related to the MRI plaque findings.
Information from the 3 stages of the study The first scan will define the prevalence of plaques in this population and allow the correlation of plaque lipid content between different plaques and with risk factors. The follow up scan after 2 years will show whether progression has occurred and the relationship of plaque characteristics with changes in risk factors. Long term follow up by questionnaire will help to show the relationship of plaque characteristics with clinical vascular events.
A proportion of time of 4 staff will be required to run this project: Clinician, physicist, nurse and driver. Others will be involved in development work.
The preliminary work required for this protocol will be completed in the second half of 1996.
Atherosclerosis natural history
And over 2 years:
There are no known hazards of MRI for the asymptomatic subjects in this protocol. Standard exclusions to MRI will be observed including the presence of pacemakers, cerebral aneurysm clips and ocular metallic deposits. Subjects will routinely answer a standard questionnaire to determine these details. Claustrophobia occurs occasionally and subjects may refuse the scan at any time if they are uncomfortable with the procedure. The presence of a clinician, nurse and resuscitation equipment on the bus will allow immediate treatment for any coincidental medical emergency.
Subjects will be asked for written informed consent prior to imaging.
Subject information prior to scanning The asymptomatic subjects will be informed that they are participating in a research project whose objective is the development of clinical experience and techniques in the imaging of the arterial wall as a marker of occult atherosclerosis. Subjects will be informed that the techniques are under evaluation and that they should not necessarily anticipate any personal benefit from the scanning. Subjects will be asked whether they wish to be shown the results of the scan (given the uncertainties associated with the clinical interpretation of the imaging findings).
Subject information after scanning Subjects will be informed of the technical result of their scan and invited to review their images on the computer console. It is hoped that this positive feedback will encourage subjects to return for the repeat scan in 2 years. It is not anticipated that severe atherosclerosis will be detected in this asymptomatic population, and questions regarding the significance of the results will in general be managed by the clinician with conventional advice regarding lifestyle modification of well established risk factors (such as smoking, exercise, obesity etc). In the event that severe atherosclerosis is identified such that the clinician believes that the findings cannot be dealt with in this way, the findings will be discussed with the subject and permission sought from the subject for clinical referral to an appropriate physician (such as the patient’s GP) for further management.
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