Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques - Implications for plaque stabilization

Background--The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Methods and Results--Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid Plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2 +/-8.4% versus 23.9 +/- 21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.3<plus/minus>3.6% versus 22.0 +/-6.5%, P<0.001), fewer macrophages (15.0<plus/minus>10.2% versus 25.3 +/- 12.5%, P<0.05), fewer T cells (11.2<plus/minus>9.3% versus 24.3 +/- 13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.6<plus/minus>3.9% versus 8.4 +/-5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.0<plus/minus>6.2% versus 3.1 +/-3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.4<plus/minus>3.1% versus 7.5 +/-3.5%, P<0.005), Cell death by TUNEL staining was reduced in the pravastatin group (17.7<plus/minus>7.8% versus 32.0 +/- 12.6%, P<0.05). Conclusions--Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.