Abstract Body (Do not enter title and authors here): BACKGROUND: Coronary heart disease (CHD) remains the primary cause of mortality and morbidity in the USA. Although rodents are widely used to explore mechanisms, they have major biological differences with humans. Pigs develop CHD similar to humans, and pigs are the FDA-preferred species for testing anti-atherosclerotic drugs. Pigs with familial hypercholesterolemia (FH pigs) are known to develop advanced atheromas containing thin fibrous caps, and large necrotic cores. However, little is known about the porcine plaque phenotype and whether pigs develop a full range of coronary plaques similar to humans.
AIMS: To quantify the distribution of porcine coronary plaque types, assess plaque morphology and cellular composition to obtain insights into mechanisms of atherosclerosis in a large animal model and to facilitate development of new therapies.
METHODS: Right coronary and left anterior descending arteries were dissected from FH pig hearts (n=9), each artery split into 6 fragments and a total of 108 vascular fragments were used to obtain cross-sections. The sections were stained with Trichrome to quantify intima/media thickness ratio (IMT), medial and necrotic core areas. The sections were also used for immunohistochemistry with cell marker antibodies (to measure % plaque smooth muscle cells (SMC), macrophages (MF), and endothelial cells (EC)). Cell apoptosis was assessed by TUNEL assay.
RESULTS: All vascular fragments were classified into 4 groups based on IMT (from A to D). Increase in IMT significantly correlated with elevation in total vessel area (A: 3.8mm² to D: 7.2mm²), increase in necrotic core area (B: 13.8% to D: 30.7%), elevation in plaque MF (A: 16.7% to D: 22.5%), increase in plaque cell apoptosis (A: 5.2% to D: 17.4% apoptotic cells) and with thinning of vascular media (A:1.3mm² to D: 0.74mm²), decrease in number of plaque SMC (A: 62.5% to D:17.9%) and plaque EC (A:3.21% to D:1.48%). We assigned each porcine plaque group to the corresponding type of human plaque: A, human type III, early lesions, 28% of all coronary plaques; B, type III/IV, fibrous plaque, 43%; C, type V, fibroatheroma, 16%; D, type VI, complicated lesions, 13%.
CONCLUSIONS: Like humans, pigs develop plaques that range from early lesions to advanced atheromas resembling type III-type VI lesions. These findings provide a rationale to use FH pigs to test the effect of novel anti-atherosclerotic drugs on the full range of coronary plaques mimicking human settings.