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The effect of melagatran, the active form of the oral direct thrombin inhibitor Ximelagatran, was investigated on atherosclerotic plaque rupture in the brachiocephalic artery of the fat-fed apolipoprotein E (apoE) knockout mice. This site develops plaque ruptures after just 8 weeks of fat feeding (Johnson et al, Circulation. 2005 Mar 22;111(11):1422-30). Eighty male apoE knockout mice, 6-8 weeks old, were fed a diet containing 21% fat and 0.15% cholesterol for 8 weeks. Forty mice were treated with 500umol/kg body weight/day of melagatran throughout the 8 weeks. The brachiocephalic artery was removed following perfusion fixation with formalin at a constant pressure of 100mmHg and embedded in paraffin. Computerized morphometry of serial sections was used to measure the areas of the plaque, the media and the lumen. The number of buried fibrous layers within the plaque and presence or absence of acute plaque rupture was also recorded. Immunostaining was used to detect the expression of markers of inflammation and thrombogenicity. Melagatran treatment significantly reduced plaque size from 38.5 ± 5.6 to 7.3 ± 1.3 x 103 μm2 (-81%; p<0.001) and the incidence of plaque ruptures from 0.43 ± 0.10 to 0.10 ± 0.05 (-77%; p<0.05). Immunohistochemical analysis of serial sections showed reduced staining for various inflammatory and thrombogenic markers. This study supports the hypothesis that serial accumulation of thrombus through repeated episodes of non-fatal plaque rupture contributes to atherosclerotic plaque growth in the apoE knockout mouse and also that inhibition of thrombin activity may be a useful strategy for inhibiting plaque rupture.
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J. Vasc. Biol. 42, Sup:2 (2005) p112