Cholesterol crystals cause mechanical damage to biological membranes: A proposed mechanism of plaque rupture and erosion leading to arterial thrombosis

Abstract

SummaryBackground: Plaque rupture and/or erosion is the leading cause of cardiovascular events; however, the process is not well understood. Although certain morphologic characteristics have been associated with ruptured plaques, these observations are of static histological images and not of the dynamics of plaque rupture. To elucidate the process of plaque rupture, we investigated the transformation of cholesterol from liquid to solid crystal to determine whether growing crystals are capable of injuring the plaque cap.Hypothesis: We hypothesized that during cholesterol crystallization the spatial configuration rapidly changes, causing forceful expansion of sharp-edged crystals that can damage the plaque cap.Methods: Two experiments were performed in vitro: first, cholesterol powder was melted in graduated cylinders and allowed to crystallize at room temperature. Volume changes from liquid to solid state were measured and timed. Second, thin biological membranes (20-40 µm) were put in the path of growing crystals to determine damage during crystallization.Results: As cholesterol crystallized, the peak volume increased rapidly by up to 45% over 3 min and sharp-tipped

Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events‐a novel insight into plaque rupture by scanning electron microscopy

“…This study proposes to explore a novel mechanism based on physical alterations within the plaque that may lead to rupture and/or erosion. These changes are related to the alteration in the physical state of the plaque content, primarily cholesterol, as was recently demonstrated by Abela and Aziz (2005).…”

IL-22 is induced by S100/calgranulin and impairs cholesterol efflux in macrophages by downregulating ABCG1

“…Reduced hydrolytic capability of the liposomes or reduced cholesterol effl ux out of the cells via reduced cholesterol transporter activity leads to accumulation of free cholesterol within the foam cells ( 24 ). As early lesions develop to advanced lesions, free cholesterol crystals form (40)(41)(42), and these have been suggested to contribute to plaque rupture and subsequent thrombosis ( 43,44 ).…”

Multiplex Coherent Anti-Stokes Raman Spectroscopy Images Intact Atheromatous Lesions and Concomitantly Identifies Distinct Chemical Profiles of Atherosclerotic Lipids

“…It is also noteworthy that the presence of lipid crystals in the solid state may enhance plaque vulnerability by inducing a nonuniform mechanical stress distortion in an atherosclerotic plaque, leading to ECM fracture. 21,27 We extensively applied a distinguishing feature of CARS to monitor chemical profile changes of atherosclerotic plaques by testing the effects of statin therapy on atherosclerotic lipids (Figure 6). The pleiotropic role of statins on plaque stabilization has been reported by various approaches based on antiinflammatory function, 28,29 an overall reduction of lipids, 30 or decrease of matrix metalloproteinases.…”

“…This is the first report in which ex vivo lipid crystals have been imaged by CARS with simultaneous chemical profiling analysis, rather than by in vitro or dissection imaging using polarized light microscopy. 8,21 The representative CARS images of atherosclerotic lipids were validated by whole-mount immunohistochemistry, showing the potential of CARS to image lipid-laden macrophages in a label-free manner. Additionally, we demonstrated the superiority of this methodology in comparison to oil red O staining.…”