Although the detailed pathophysiologic triggers responsible for the individual natural history trajectory of each atherosclerotic plaque are unknown, the local, dynamic interplay between low endothelial shear stress (ESS) and vascular inflammation is likely to be critical. The purpose of the proposed project is to combine ESS with inflammation in a plaque risk classification scheme aiming to predict high-risk plaque at early stages of its development before its rupture. Enhancing our understanding of the magnitude of local hemodynamic stimulus with respect to inflammation (i.e. ESS), as well as the extent of local inflammation would allow us to detect early, minimally stenotic, atherosclerotic lesions and stratify the risk of them evolving into high-risk plaques. The latter classification is of utmost clinical importance as it can provide a rationale for innovative diagnostic and/or therapeutic strategies for the management of coronary patients, as well as the prevention of acute coronary syndrome. Identification of a high-risk plaque at its early stages of development would potentially justify highly selective, prophylactic local interventions, such as implantation of stents or targeted nanoparticle-based delivery of anti-inflammatory drugs, supplemented by an intensive systemic pharmacologic approach to limit the severity of inflammation, stabilize the plaque, and thereby avert a future acute coronary event. The clinical and economic implications of identifying and treating high-risk individual coronary lesions before an adverse cardiac event can occur are anticipated to be enormous.