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Local hemodynamic factors are major determinants of the natural history of individual atherosclerotic plaque progression in coronary arteries. The purpose of this review is to summarize the role of low endothelial shear stress (ESS) in the transition of early, stable plaques to high-risk atherosclerotic lesions.Low ESS regulates multiple pathways within the atherosclerotic lesion, resulting in intense vascular inflammation, progressive lipid accumulation, and formation and expansion of a necrotic core. Upregulation of matrix-degrading proteases promotes thinning of the fibrous cap, severe internal elastic lamina fragmentation, and extracellular matrix remodeling. In the setting of plaque-induced changes of the local ESS, coronary regions persistently exposed to very low ESS develop excessive expansive remodeling, which further exacerbates the proinflammatory low ESS stimulus. Recent studies suggest that the effect of recognized cardioprotective medications may be mediated by attenuation of the proinflammatory effect of the low ESS environment in which a plaque develops.Low ESS determines the severity of vascular inflammation, the status of the extracellular matrix, and the nature of wall remodeling, all of which synergistically promote the transition of stable lesions to thin cap fibroatheromata that may rupture with subsequent formation of an occlusive thrombus and result in an acute coronary syndrome.