A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture

Abstract

The role of microcalcifications (μCalcs) in the biomechanics of vulnerable plaque rupture is examined. Our laboratory previously proposed (Ref. 44), using a very limited tissue sample, that μCalcs embedded in the fibrous cap proper could significantly increase cap instability. This study has been greatly expanded. Ninety-two human coronary arteries containing 62 fibroatheroma were examined using high-resolution microcomputed tomography at 6.7-μm resolution and undecalcified histology with special emphasis on calcified particles <50 μm in diameter. Our results reveal the presence of thousands of μCalcs, the vast majority in lipid pools where they are not dangerous. However, 81 μCalcs were also observed in the fibrous caps of nine of the fibroatheroma. All 81 of these μCalcs were analyzed using three-dimensional finite-element analysis, and the results were used to develop important new clinical criteria for cap stability. These criteria include variation of the Young's modulus of the μCalc and surrounding tissue, μCalc size, and clustering. We found that local tissue stress could be increased fivefold when μCalcs were closely spaced, and the peak circumferential stress in the thinnest nonruptured cap (66 μm) if no μCalcs were present was only 107 kPa, far less than the proposed minimum rupture threshold of 300 kPa. These results and histology suggest that there are numerous μCalcs < 15 μm in the caps, not visible at 6.7-μm resolution, and that our failure to find any nonruptured caps between 30 and 66 μm is a strong indication that many of these caps contained μCalcs.

Endothelial Shear Stress and Coronary Plaque Characteristics in Humans

“…Although the role of superficial calcium deposits in atherosclerosis is not fully characterized, focal superficial calcifications represent the underlying morphology of calcified nodules, the third most common cause of ACS, 26 and recent studies suggest a role of superficial microcalcification in increasing the mechanical stress on thin fibrous cap. 27 Furthermore, we found that the presence of spotty calcifications tended to be more frequent in areas with low ESS. Spotty calcific deposits have been associated with more extensive and diffuse coronary atherosclerosis and accelerated disease progression, 18 and a recent OCT study showed a positive correlation between the number of spotty calcium deposits and plaque rupture.…”

Pathology of Coronary Atherosclerotic Plaques and Mechanisms of Plaque Disruption

“…Microcalcification within the fibrous cap may predispose to rupture, due to substantial stress accumulation within the fibrous cap (27 nodules is still controversial, and though intraplaque hemorrhages were not described in this article, they may contribute to necrotic core expansion and plaque instability.…”

Optical measurement of arterial mechanical properties: from atherosclerotic plaque initiation to rupture

“…23,35 More recent studies, however, challenge the <65 μm cap thickness criterion, indicating that caps >100 μm often rupture at stress levels far lower than the 300-kPa threshold. [90][91][92] The inability to explain plaque rupture in thick caps has prompted a number of FEA studies to test other biomechanical factors of cap rupture that include necrotic core composition, thickness and angle, 16,24,25,93 residual stress distribution, 94 and the presence and location of microcalcifications in the fibrous cap. 90 Collectively, these studies showed that (1) the presence of a large necrotic core elevated peak cap stress and increased the risk of rupture, 25 (2) cholesterol constituents of the lipid pool modulated peak stress distribution, 16 (3) residual stress influenced the extent and location of peak stress, and (4) peak stress could be elevated by fivefold in the presence of microcalcifications.…”