A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps

Yuliya Vengrenyuk, Stéphane Carlier, Savvas Xanthos, Luis Cardoso, Peter Ganatos, Renu Virmnani, Shmuel Einav, Lane Gilchrist, Sheldon Weinbaum

Research output: Contribution to journalArticlepeer-review

411 Scopus citations

Abstract

In this article, we advance a hypothesis for the rupture of thin fibrous cap atheroma, namely that minute (10-μm-diameier) cellular-level microcalcifications in the cap, which heretofore have gone undetected because they lie below the visibility of current in vivo imaging techniques, cause local stress concentrations that lead to interfacial debonding. New theoretical solutions are presented for the local stress concentration around these minute spherical inclusions that predict a nearly 2-fold increase in interfacial stress that is relatively insensitive to the location of the hypothesized microinclusions in the cap. To experimentally confirm the existence of the hypothesized cellular-level microcalcifications, we examined autopsy specimens of coronary atheromatous lesions using in vitro imaging techniques whose resolution far exceeds conventional magnetic resonance imaging, intravascular ultrasound, and optical coherence tomography approaches. These high-resolution imaging modalities, which include confocal microscopy with calcium-specific staining and micro-computed tomography imaging, provide images of cellular-level calcifications within the cap proper. As anticipated, the minute inclusions in the cap are very rare compared with the numerous calcified macrophages observed in the necrotic core. Our mathematical model predicts that inclusions located in an area of high circumferential stress (>300 kPa) in the cap can intensify this stress to nearly 600 kPa when the cap thickness is <65 μm. The most likely candidates for the inclusions are either calcified macrophages or smooth muscle cells that have undergone apoptosis.

Original languageEnglish
Pages (from-to)14678-14683
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number40
DOIs
StatePublished - 3 Oct 2006
Externally publishedYes

Keywords

  • Cellular-level calcification
  • Stress concentration
  • Thin-cap fibroatheroma

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