A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps - PubMed (original) (raw)

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

Yuliya Vengrenyuk et al. Proc Natl Acad Sci U S A. 2006.

Abstract

In this article, we advance a hypothesis for the rupture of thin fibrous cap atheroma, namely that minute (10-mum-diameter) 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 microm. The most likely candidates for the inclusions are either calcified macrophages or smooth muscle cells that have undergone apoptosis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Mathematical model: geometry and coordinate system. Shown is a perfectly bonded rigid spherical inclusion with radius a in a fibrous cap.

Fig. 2.

Fig. 2.

Stress concentration in a fibrous cap due to the presence of a rigid spherical inclusion. (A) Distribution of radial stress concentration, σr/_T_0, at the matrix–inclusion interface for the cases of a = 0.1, a = 0.5, and c = 0, 0.4 (φ = 0°). (B) Effect of a free surface on factor of stress concentration for a = 0.1, 0.2, 0.3, 0.4, 0.5, and 0.6.

Fig. 3.

Fig. 3.

Changes in cap PCS with cap thickness for the case when cap tissue is homogeneous (line 1) and when it contains a rigid inclusion 10 and 20 μm in diameter (lines 2 and 3, respectively).

Fig. 4.

Fig. 4.

Confocal microscopy images of calcific deposits stained with Alizarin red S in coronary artery lesions. (A) Numerous cellular- (≈10 μm) and subcellular-level calcifications in the necrotic core. (B) Overlay of A with a transmission image. (C) Calcified inclusions in the fibrous cap appear red in a section stained with Alizarin red S. (D) A 3D confocal imaging reconstruction of section C within the slide thickness.

Fig. 5.

Fig. 5.

Micro-CT detection of cellular-level microcalcifications in a fibrous cap. (A) Sagittal view of a coronary artery segment with microcalcifications in the thick cap (35-μm resolution). (B) A cross-section of the lesion (arrow in A) corresponding to the plane marked by an arrow in A with cellular-level microcalcifications ≈10- to 20-μm diameter in the cap (circled) and numerous calcific deposits at the bottom of the lipid pool shown by arrows (7-μm resolution).

References

    1. Falk E. Circulation. 1992;86(Suppl 3):30–42. - PubMed
    1. Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerosis. 1991;87:87–90. - PubMed
    1. Libby P. Circulation. 1995;91:2844–2850. - PubMed
    1. Little WC. Am J Cardiol. 1990;66:44G–47G. - PubMed
    1. Muller JE, Tofler GH. Ann Epidemiol. 1992;2:393–405. - PubMed

MeSH terms

LinkOut - more resources