Student: Marta Dazzi
Excessive uptake of plasma macromolecules by the arterial wall is thought to be a key event in the initiation and progression of atherosclerosis but has been little studied in vivo because of technical challenges. Of the handful of labs worldwide that can make such measurements, two (one at Imperial and one at KCL) are associated with the CDT and use image-based methods. Bringing them together will allow the resolution of two critical unsolved problems: whether uptake of plasma macromolecules by human arteries is the same as uptake already measured in animal arteries, and whether uptake by the clinically-important but mechanically-unique coronary arteries is the same as uptake by non-coronary arteries. It will also allow improvement of the methods and investigation of mechanisms underlying elevated uptake. Ultimately it could lead to novel strategies for risk stratification and intervention. Inter-group collaboration stimulated by co-supervising a student would lead to joint grant applications.
Cardiovascular disease is the major cause of mortality and morbidity in developed countries. The underlying pathology in most cases is atherosclerosis and lipid accumulation in the wall appears to be the key initiating event. The lipid – principally cholesterol – derives from lipoproteins circulating in the blood. This explains why a high plasma concentration of cholesterol (or its chief carrier, low density lipoprotein (LDL)) is a major risk factor, why lipid-lowering drugs reduce or reverse disease progression, and why atherosclerosis can be induced in animals by dietary or genetic elevation of circulating cholesterol.
Despite its obvious importance, transport of LDL from blood into the wall is poorly understood; for example, it is not even clear whether LDL enters the wall through or between the endothelial cells that line it. Only a handful of labs worldwide study these transport processes in vivo, reflecting the technical difficulty of doing so. Remarkably, the leaders of two of these labs are both members of the CDT in Medical Imaging, giving it an internationally-unique opportunity to excel in this area: Weinberg and Botnar have independently developed and applied image-based methods for investigating arterial wall mass transport in laboratory animals. Both methods are based on studying the movement of albumin, an inert macromolecular marker that avoids the metabolic complications associated with using LDL itself. The Weinberg lab uses fluorescently labelled albumin; after moving into the wall in vivo, this tracer is fixed and its distribution in excised vessels is imaged in 3-D by tile-scanning confocal microscopy. The method allows sub-micron resolution and accurate, absolute quantification. The Botnar lab uses a gadolinium-based, albumin-targeting agent that can be imaged by MRI (resolution = 100 μm) in vivo. The method additionally permits concurrent MR imaging of other, related phenomena such as blood flow characteristics and, most importantly, its non-invasive character means it can be used to measure blood protein transport across the endothelium in people.
The CDT provides an ideal opportunity to bring together these groups for the first time to compare their methods and to combine them. This will permit investigation of two critical unsolved problems: whether uptake of plasma macromolecules by human arteries is the same as uptake by animal arteries, and whether uptake by coronary arteries is the same as uptake by non-coronary arteries. Uptake by human arteries was investigated in the 1970s but, in the absence of non-invasive techniques, these experiments had to be conducted in terminally ill patients, with arteries being harvested after death. Uptake was an order of magnitude higher than in animal experiments – it is unclear whether this reflects the poor health of the patients or unexpected unique properties of human vessels. Only preliminary results are available for coronaries. Again, it is unclear whether uptake in these vessels – the arteries of greatest clinical significance – differs from uptake elsewhere, perhaps reflecting their unique mechanical environment and explaining their particular susceptibility to disease.