LDL Hypercholesterolemia Is Associated With Accumulation of Oxidized LDL, Atherosclerotic Plaque Growth, and Compensatory Vessel Enlargement in Coronary Arteries of Miniature Pigs

From the Center for Molecular and Vascular Biology (P.H., G.T., D.C.) and the Center for Experimental Surgery and Anaesthesiology (B.S., W.F.), University of Leuven, Leuven, Belgium.

Correspondence to Paul Holvoet, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000, Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be

Abstract—The association between accumulation of oxidized low density lipoprotein (LDL) and (1) progression of atherosclerotic plaques and (2) compensatory enlargement was assessed in the coronary arteries of LDL-hypercholesterolemic miniature pigs. In miniature pigs fed a 4% cholesterol diet, LDL cholesterol levels increased from 27±3.5 mg/dL (mean±SEM, n=36) to 250±28 mg/dL (n=10), 260±15 mg/dL (n=6), and 260±17 mg/dL (n=10) at 6, 14, and 24 weeks, respectively. Mean intimal areas of lesions in the left anterior descending coronary artery of hypercholesterolemic pigs were 0.16±0.046 mm² at 6 weeks (n=10) and increased 5.4-fold (n=6, P<.05) and 10.6-fold (n=10, P<.001) at 14 and 24 weeks, respectively. Plaque growth was associated with an increase in mean internal elastic lamina area, from 1.44±0.17 to 4.38±0.52 mm² (P=.007) and in mean luminal area from 1.42±0.15 mm² in control pigs to 4.38±0.52 mm² in pigs fed a cholesterol diet for 24 weeks (P=.007 vs control). Levels of total LDL in the intima, measured immunocytochemically, were 0.031±0.0098, 0.11±0.057 (P.05), and 0.43±0.082 U (P<.001) at 6, 14, and 24 weeks, respectively. Corresponding levels of oxidized LDL were 0.034±0.023, 0.11±0.050 (P<.05), and 0.44±0.065 U (P<.001), respectively, suggesting that virtually all LDL in the intima is oxidized. Levels of oxidized LDL in the lesions were correlated with the intimal areas (r=.85, P<.0001) but were independent of plasma levels of LDL cholesterol and of oxidized LDL. Plaque levels of oxidized LDL were also correlated with internal elastic lamina areas (r=.72, P<.0001) and with luminal areas (r=.50, P=.0098). Plaque growth in the coronary arteries of LDL-hypercholesterolemic miniature pigs is associated with (1) an increase in plaque levels of oxidized LDL at constant plasma levels of LDL cholesterol and of oxidized LDL and (2) compensatory vessel enlargement proportional to plaque levels of oxidized LDL.

Key Words: coronary atherosclerosis • oxidized LDL • plaque growth • remodeling

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