Hyperlipidemia promotes thrombosis after injury to atherosclerotic vesselsin apolipoprotein E-deficient mice

The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well established. Cholesterol-lowering therapies lead t o a decrease in the incidence of vascular thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the occurren ce of acute thrombosis overlying a disrupted plaque is influenced by change s in lipid levels, The influence of acute hyperlipidemia on the development of thrombosis overlying an atherosclerotic plaque in vivo has not been ext ensively studied. We used a murine model of vascular injury induced by a ph otochemical reaction to elicit thrombus formation overlying an atherosclero tic plaque. Fifteen apolipoprotein E-deficient mice were maintained on norm al chow until the age of 30 weeks. Five days before the induction of thromb osis, 6 mice were stal ted on a high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical injury to the common caroti d artery immediately proximal to the carotid bifurcation, where an atherosc lerotic plaque is consistently present. Mice maintained on normal chow deve loped occlusive thrombi, determined by cessation of blood flow, 44 +/- 5 mi nutes (mean +/- SEM) after photochemical injury, whereas mice fed a high fa t chow developed occlusive thrombosis at 27 +/- 3 minutes (P < 0.02), Histo logical analysis confirmed the presence of acute thrombus formation overlyi ng an atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol facilitate thrombus fo rmation at sites of atherosclerosis after vascular injury.