Background-Native atherosclerosis and in-stent restenosis are focal and evolve independently. The endothelium controls local arterial responses by transduction of shear stress. Characterization of endothelial shear stress (ESS) may allow for prediction of progression of atherosclerosis and in-stent restenosis. Methods and Results-By using intracoronary ultrasound, biplane coronary angiography, and measurement of coronary blood flow, we represented the artery in accurate 3D space and determined detailed characteristics of ESS and arterial wall/plaque morphology. Patients who underwent stent implantation and who had another artery with luminal obstruction Ͻ50% underwent intravascular profiling initially and after 6-month follow-up. Twelve arteries in 8 patients were studied: 6 native and 6 stented arteries. In native arteries, regions of abnormally low baseline ESS exhibited a significant increase in plaque thickness and enlargement of the outer vessel wall, such that lumen radius remained unchanged (outward remodeling). Regions of physiological ESS showed little change. Regions with increased ESS exhibited outward remodeling with normalization of ESS. In stented arteries, there was an increase in intima-medial thickness, a decrease in lumen radius, and an increase in ESS at all levels of baseline ESS. Key Words: endothelium Ⅲ atherosclerosis Ⅲ coronary disease Ⅲ shear stress C oronary atherosclerosis is focal and eccentric, 1,2 and each coronary obstruction progresses or regresses in an independent manner, including areas after percutaneous revascularization. 3 Local hemodynamic factors are crucial to determine the evolution of coronary obstructions. 1,4 The vascular endothelium is in a pivotal position to respond to the dynamic forces acting on the vessel wall owing to the complex 3D geometry of the artery. 5 Fluid shear stresses elicit a large number of responses in endothelial cells. 4,5 The response of genes sensitive to local hemodynamic forces likely leads to creation of a raised plaque; subsequent hemodynamic forces created by the plaque may lead to a cycle of cellular recruitment and proliferation, lipid accumulation, and inflammation. 4,6 The pathobiology of restenosis after percutaneous coronary interventions may be due to 2 independent processes: geometric remodeling and neointimal hyperplasia. In segments undergoing angioplasty alone, late lumen loss is largely due to geometric remodeling, whereas in stented arteries, late lumen loss correlates primarily with intimal hyperplasia. 7 The effect of endothelial shear stress (ESS) within the stent or at the stent edges has not been fully explored as a mechanism contributing to in-stent restenosis. 8 Current methodologies cannot provide adequate information about the microenvironment of the coronary arteries. We developed a unique system by using coronary intravascular ultrasound (IVUS), biplane coronary angiography, and measurements of coronary blood flow to represent the artery in accurate 3D space and to produce detailed characteristics of ESS and arter...