The quantitative assessment of atherosclerosis was pioneered in studies performed in the rabbit. Both cholesterol-fed and mutant rabbit strains have provided models to generate new therapeutic modalities. The use of quantitative planimetry and quantitative histopathology are the gold standard for investigation of both the pathophysiology as well as antiatherogenic therapy. We have undertaken the extension of new diagnostic modalities to quantitatively assess atherogenesis in the rabbit in vivo. The goals of this project are two-fold. First, by using in vivo methods, the rate of progression of disease can be directly assessed in the rabbit and establishing their utility, these techniques can be extended to man. The current cardiac catheterization methods evaluate the vascular lumen rather than the arterial wall itself, which is the site of the atherogenic process. We have undertaken the systematic evaluation of the established techniques of quantitative planimetry and quantitative histopathology and compared them to new, promising methods. We have performed intravascular ultrasound, magnetic resonance imaging, the residual strain measurements in control, Watanabe, and transgenic rabbits. We have established that intravascular ultrasound detects atherosclerosis at the earliest stages. Thereafter, flow pattern changes, detect by magnetic resonance imaging, are observed. Finally, actual increases in wall thickness as well as the development of plaques can be detected. These in vivo techniques are useful in characterizing the development of arterial lesions in our transgenic rabbit program. The parallel application of these techniques in our patients homozygous for familial hypercholesterolemia has also been initiated. Therefore the refinement of these methods in this animal model system will not only permit the investigation of transgene expression on atherogenesis, but this technology development will enhance the ability to evaluate human atherogenesis.
