Abstract 12777: Pleiotropic Effects of Statin in Stabilization of Unstable Coronary Plaque - Direct Evidence from Low Density Lipoprotein Receptor Knockout Pig
Background: Lipid-lowering therapy with statins reduces the risk of cardiovascular events indicating that statins may stabilize coronary vulnerable plaque. However, no animal experiments have confirmed this hypothesis and the underlying mechanisms are still unknown. We developed a low density lipoprotein receptor knockout (LDLR-/-) pig with complex unstable coronary plaque and examined whether statin stabilize unstable plaque.
Methods and Results: LDLR-/- pigs were generated by targeted deletion of LDLR exon regions using transgenic and cloning techniques. When LDLR-/- pigs were fed with high cholesterol and high fat (HCHF) diet, complicated unstable plaque with positive remodeling developed in the coronary arteries. Pitavastatin (40mg / day) was administered orally for 4 months to LDLR-/- pigs with HCHF diet. Compared to control (HCHF diet only), pitavastatin tended to decrease 9.9% of total cholesterol (942 ± 119 vs. 1045 ± 42 mg / dl, P=0.46), 16.1% of LDL (549 ± 55 vs. 654 ± 33 mg / dl, P=0.175), and increase 4.7% of high density lipoprotein (67 ± 5 vs. 64 ± 4 mg / dl, P=0.66) without significances. Volumetric intravascular ultrasound analysis revealed 52% reduction of plaque volume in pitavastatin treated pigs (248 ± 33 vs. 520 ± 119 mm3, length modified, P=0.04). After euthanasia, coronary arteries were harvested and sliced transversely at 1-cm intervals from the proximal to the distal for histopathological assessment. Compared to the huge amount of foam cells-riched necrotic plaque with thin fibrous cap in control pigs, pitavastatin treated pigs exhibited moderated smooth muscle cells-riched plaque with thick fibrous cap. Intra-plaque hemorrhage and calcification deposition were also significantly ameliorated with pitavastatin treatments. Furthermore, pitavastatin dramatically inhibited inflammatory cells infiltration in plaque. The detailed effects of statin in inflammation in unstable plaque are under investigation.
Conclusions: This study provided direct evidences of statin in stabilization of unstable coronary plaque in large animal experiments. Statin may stabilize unstable plaque through other mechanisms in addition to its lipid-lowering effects.
- © 2013 by American Heart Association, Inc.