The microenvironment of the atheroma expresses phenotypes of plaque instability.

• Histopathology and intravascular imaging show that a stable atheroma undergoes one of several phenotypic changes to become destabilized and at risk for occlusive luminal thrombosis. • An unstable plaque associated with clinical luminal thrombosis manifests one of several phenotypes, including erosion, fibrous cap rupture, nodular calcification and rupture, and cap rupture overlying single or multiple layers of previous cap "rupture-and-repair." • The phenotypes are characterized by altered hemodynamic shear stress, prominent endothelial denudation and dysfunction, smooth muscle cells phenotypic changes, fibrous cap remodeling, expansion, and growth of the vasa vasorum, activation of adventitial and perivascular adipose tissue cells, and alteration in chronic inflammation and lipid deposition. • There are no adequate animal models to study the transition of stable to unstable atheromas to validate the numerous pathogenic steps that have been suggested based on human studies. • Advancement in noninvasive imaging is essential to understand atheroma destabilization and establish plaque burden in vulnerable patients. Data from histopathology studies of human atherosclerotic tissue specimens and from vascular imaging studies support the concept that the local arterial microenvironment of a stable atheroma promotes destabilizing conditions that result in the transition to an unstable atheroma. Destabilization is characterized by several different plaque phenotypes that cause major clinical events such as acute coronary syndrome and cerebrovascular strokes. There are several rupture-associated phenotypes causing thrombotic vascular occlusion including simple fibrous cap rupture of an atheroma, fibrous cap rupture at site of previous rupture-and-repair of an atheroma, and nodular calcification with rupture. Endothelial erosion without rupture has more recently been shown to be a common phenotype to promote thrombosis as well. Microenvironment features that are linked to these phenotypes of plaque instability are neovascularization arising from the vasa vasorum network leading to necrotic core expansion, intraplaque hemorrhage, and cap rupture; activation of adventitial and perivascular adipose tissue cells leading to secretion of cytokines, growth factors, adipokines in the outer artery wall that destabilize plaque structure; and vascular smooth muscle cell phenotypic switching through transdifferentiation and stem/progenitor cell activation resulting in the promotion of inflammation, calcification, and secretion of extracellular matrix, altering fibrous cap structure, and necrotic core growth. As the technology evolves, studies using noninvasive vascular imaging will be able to investigate the transition of stable to unstable atheromas in real time. A limitation in the field, however, is that reliable and predictable experimental models of spontaneous plaque rupture and/or erosion are not currently available to study the cell and molecular mechanisms that regulate the conversion of the stable atheroma to an unstable plaque. [ABSTRACT FROM AUTHOR]