Abstract 5100: Vulnerability of Atherosclerotic Plaque in Relation to Blood Flow Direction: Mechanisms of Increased Plaque Rupture at the Upstream Region

Abstract

Objectives: Rupture of atherosclerotic plaque, the leading cause of acute coronary syndromes and ischemic strokes, occurs mainly at the upstream (proximal) shoulder of the lesion. We investigated the mechanisms leading to plaque rupture in relation to blood flow direction. Methods: The occurrence of ulceration, endothelial erosion, intimal neovascularization, and intraplaque hemorrhage were histologically determined in 70 human carotid specimens. Longitudinal sections of the plaques were immunohistochemically analyzed for cathepsin L, mast cell chymase, 5-lipoxygenase, Bax, VEGF, and connective tissue growth factor (CTGF) using specific monoclonal antibodies. Results: In >70% of ulcerated plaques, ulceration/rupture was observed at the upstream region of the plaque. Similarly, the occurrence of active intimal neovascularization and intraplaque hemorrhage was increased in upstream region (p<0.01), whereas endothelial erosion was more frequent downstream. The mean numbers of cells positive for cathepsin L, were significantly higher upstream as compared with downstream regions of the atherosclerotic lesions (58±7 upstream vs 33.1±5 downstream; p<0.001). Similarly, the expression of chymase was markedly increased in the upstream region of the plaque (34.3±5 upstream vs 17.1±4 downstream, p<0.001, n=70). The key enzyme in leukotriene production, 5-lipoxygenase, was abundantly expressed in majority of the analyzed plaques, however, no significant differences were observed in its expression between the two plaque shoulders. Pro-apoptotic protein Bax was detected more frequently at the upstream plaque shoulder, and localized mainly to smooth muscle cells and macrophages. The immunoreactivity of CTGF and VEGF showed a very high degree of variability between different plaques, but the overall statistical analyses demonstrated a significant increase in both CTGF and VEGF expression at the upstream shoulder in majority of the analysed plaques. Conclusions: Local hemodynamic forces affect plaque stability. Rupture at the upstream region of atherosclerotic lesion is related to activation of proteolytic and pro-apototic mechanisms, as well as enhanced neovascularization and intraplaque hemorrhage.