Abstract 422: Atherosclerosis and Rage Expression by Histology and Imaging in Hyperlipidemic Pigs
Purpose and methods To characterize atherosclerotic lesions and RAGE expression in a large animal model and investigate targeting RAGE for in-vivo imaging. Nine hyperlipidemic pigs at 12 mo of age were studied. LDL averaged 513 ± 74 mg/dL and final wt was 63.3 ± 12.4 kg. Pigs were injected with 16.3 ± 3.5 mCi of 99mTc anti-RAGE F(ab’)2 and after 8 hr (blood pool clearance) underwent SPECT/CT imaging of the neck and thorax and then euthanized, the aorta including innominate, proximal carotids, and proximal ileofemoral branches and coronaries were dissected. Vascular tissue was divided into 36 anatomical segments: coronaries: 4 each x 3 = 12, aortic root: 3, aortic arch: 4, thoracic aorta: 3 and abdominal aorta: 3, each carotid and femoral: 2. Sections from each segment were counted and stained for H&E and RAGE. Scans were analyzed for tracer uptake in organs and vascular structures and counts converted in %ID. All sections were classified according to AHA criteria, % stenosis, and % RAGE staining was quantified. One HL pig received non-immune control antibody and 2 farm pigs were injected for blood pool clearance and SPECT imaging.
Results On pathological examination 75/324 segments or 23% showed class 2 lesion or greater. All class III or IV lesions were in the coronaries, carotids, and femoral arteries and % stenosis ranged from 16 to 65%. In vivo biodistribution showed intense uptake of the antibody in the lungs (15 %ID) indicating high constitutive expression of RAGE and precluded visualizing the thoracic aorta. Heart uptake was low (1.3 x 10-4 %ID) providing visualization of focal coronary uptake and the carotids were well seen. Focal tracer uptake was visualized on SPECT scans in these 2 vascular territories for all vessels with class III or IV lesions and uptake ranged from 4 -22 %ID x 10-4. Correlations were R = 0.85, P = 0.002 for %ID vs. %ID/g and R = 0.83, P = 0.002 for %ID/g vs. % RAGE staining.
Conclusions There is variability in extent and severity of atherosclerotic disease in HL pigs at one year. RAGE staining is found in all class II-IV lesions and correlated with uptake of radiolabeled antibody targeting RAGE. High RAGE expression in lungs limited imaging the aorta but carotid and coronary artery uptake was seen on SPECT scans.
- © 2013 by American Heart Association, Inc.