Friday, November 22, 2024
11/22/2024
SUMMARY Human fibroatheroma (FA) cap rupture leads to the formation of an occluding thrombus, myocardial infarction (MI) and sudden death in more than half a million Americans every year. A vulnerable plaque is defined as a positively remodeled lesion, rich in vasa-vasorum, characterized by smooth muscle cell apoptosis, and containing a lipid rich pool with a fibrous cap that is infiltrated by macrophages. The current paradigm is that a cap thickness < 65 µm (thin-cap FA or TCFA) is the key determinant of plaque vulnerability, and rupture occurs when the cap tissue experiences a peak stress greater than 300 kPa. However, there are several other factors that play an important role in the FA cap rupture, including atheroma morphology, biological environment, tissue composition and mechanical forces. Indeed, whether the cap thickness is the single most important criterion predicting plaque vulnerability is unclear, and the underlying mechanisms for atheroma cap rupture are still insufficiently understood. Vascular calcification has emerged among the factors that play an important role in the stability of plaque rupture. For many decades, cardiovascular calcification has been considered as a passive process, accompanying atheroma progression, correlated with plaque burden, and apparently without a major role on plaque vulnerability. Clinical and pathological analyses have previously focused on the total amount of calcification (calcified area in a whole atheroma cross section), and whether more calcification means higher risk of plaque rupture or not. However, this paradigm has been changing in the last decade or so. Recent research has focused on the presence of microcalcifications (µCalcs) in the atheroma, and more importantly on whether clusters of µCalcs are located in the cap of the atheroma. While the vast majority of µCalcs are found in the lipid pool or necrotic core, they are inconsequential to vulnerable plaque. We have also demonstrated to date the existence of thousands of μCalcs primarily in non-ruptured human atheroma caps using µCT imaging, and that they behave as an intensifier of the background circumferential stress in the cap. However, the similar X-ray absorption properties of a thrombus and soft tissue complicates the analysis of μCalcs in ruptured FAs. To overcome this limitation, we have developed a high-resolution contrast-enhanced µCT (CEµCT) approach to investigate whether μCalcs co-localize with the site of FA cap rupture, in cases where an occluding thrombus is formed, followed by myocardial infarction. The working hypothesis is that μCalcs in the FA cap has a major effect on the FA cap rupture threshold. To test this hypothesis we propose to (1) determine the sensitivity and specificity of μCalcs in the FA cap as a key biomarker of fibroatheroma rupture risk in human coronary vessels, and (2) to characterize the increase in FA rupture risk due to μCalcs in the ApoE KO mice. If successful, the proposed study will increase our understanding on vulnerable plaque rupture biomechanics and provide an alternative paradigm for vulnerable plaque that will consider the effect of μCalcs in human atheroma cap rupture risk.
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