Abstract 4362968: Coronary atherosclerotic plaque classification in hypercholesteremic pigs: new tool for drug discovery and testing anti-atherogenic therapies

Background: Animal models facilitate study of coronary atherosclerotic disease. Currently, there is no formalclassification of coronary plaques in the animal models. Pigs are the FDA-preferred species for testing cardiovascular devices and the primary choice for preclinical toxicological testing of anti-atherosclerotic drugs.Pigs with familial hypercholesterolemia (FH pigs) fed with high-fat diet develop early atherosclerotic lesions and complex atheromas in coronaries mimicking human disease and FH pigs are a gold standard model for translational atherosclerosis research. Methods: We isolated 104 coronary fragments from FH pigs. Intima-media thickness ratio, vessel size, necrotic core (NC) area and fibrous cap (FC) thickness were used as morphological criteria to classify plaques by K means clustering. Levels of cell type markers (α-smooth muscle actin, smooth muscle cells, SMC; scavenger receptor type A, SRA, macrophages, MF; CD31, endothelial cells, EC) were quantified by IHC. Intraplaque neovascularization, collagen levels (Trichrome staining), calcification (Von Kossa stain) and intraplaque hemorrhage (Carstairs method) were used as additional criteria and to establish the similarity of porcine plaque to human lesions. Results: We identified 4 clearly distinguishable plaque groups (A-D) in porcine coronary arteries. Plaque group A has no FC and NC, high level of SMC (>18%, as normalized per plaque area) and low MF level (<10%) consistent with the definition of intermediate (type III) human lesions in accordance with the AHA-developed histological classification of human coronary plaques. Group B has small NC area (<15%), thick FC, and large amount of intracellular lipid droplets in intima like type IV atheroma. Group C has increased vessel size (1.6-fold increase vs. group A and B, P<0.05), marked thinning of the tunica media, and a high level of collagen (>43%) mimicking type V fibroatheroma. Group D has a low level of SMC (<7%), high MF content (>15%), large NC area (>30%), multiple breaks in the endothelial layer, severe calcium deposition and neovascularization, and high vulnerability index consistent with type VI complicated lesion. Conclusions: Our results establish the suitability of hypercholesteremic pigs as a pre-clinical model closely mimicking human coronary atherosclerosis and provide researchers with an instrument to study mechanism of atherosclerosis and to assess changes in specific lesion phenotype induced by interventions.