Changing views of the biomechanics of vulnerable plaque rupture: a review

Abstract

This review examines changing perspectives on the biomechanics of vulnerable plaque rupture over the past 25 years from the first finite element analyses (FEA) showing that the presence of a lipid pool significantly increases the local tissue stress in the atheroma cap to the latest imaging and 3D FEA studies revealing numerous microcalcifications in the cap proper and a new paradigm for cap rupture. The first part of the review summarizes studies describing the role of the fibrous cap thickness, tissue properties, and lesion geometry as main determinants of the risk of rupture. Advantages and limitations of current imaging technologies for assessment of vulnerable plaques are also discussed. However, the basic paradoxes as to why ruptures frequently did not coincide with location of PCS and why caps >65 μm thickness could rupture at tissue stresses significantly below the 300 kPa critical threshold still remained unresolved. The second part of the review describes recent studies in the role of microcalcifications, their origin, shape, and clustering in explaining these unresolved issues including the actual mechanism of rupture due to the explosive growth of tiny voids (cavitation) in local regions of high stress concentration between closely spaced microinclusions oriented along their tensile axis.

Figure 1

The tissue over the lipid pools is rich in SMCs and proteoglycans, some scattered macrophages, and lymphocytes may also be present. The more definitive lesions, of fibrous cap atheroma, classically shows a true necrotic core (NC) containing cholesterol esters, free cholesterol, phospholipids, and triglycerides. The fibrous cap consists of SMCs in a proteoglycan–collagen matrix, with a variable number of macrophages and lymphocytes. The thin-cap fibroatheroma (vulnerable plaque): thin-cap fibroathomas are lesions with large necrotic cores containing numerous cholesterol clefts. The overlying fibrous cap (FC) is thin (< 65 μm) and heavily infiltrated by macrophages; SMCs are rare and microvessels are generally present in the adventitia. (Reproduced with permission from Virmani R, et al., Arteriosclero Thromb Vasc Biol 2000;20:1262 75.3).

Figure 2

μCT detection of cellular-level microcalcifications in a fibrous cap. A cross-section of the lesion with cellular-level microcalcifications ~15 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). (Reproduced with permission from Vengrenyuk et al., Proc Natl Acad Sci U S A 2006 103(40):14678-14683).

Figure 3

Changes in cap peak circumferential stress (PSC) with cap thickness for the case when cap tissue is homogeneous (line 1) and when it contains a rigid inclusion of 10 and 20 μm in diameter (lines 2 and 3 respectively). (Reproduced with permission from Vengrenyuk et al., Proc Natl Acad Sci U S A 2006 103(40):14678-14683).

Figure 4

Calculated cavitation and debonding stress threshold vs. diameter of μCalc (θ = 5°, G_a = 0.5 J/m²). Figure shows that for μCalcs < 70μm σ_c < σ_d, and cavitation should be the preferential mode of failure (rupture of the fibrous cap), and for very small calcifications D < 5μm no cavitation nor debonding would occur. Solid horizontal lines indicate minimum and average rupture thresholds 300kP and 545kPa (Cheng et al. 1993). (Reproduced with permission from Maldonado et al., J Biomech 2012 46(2):396-401).

Figure 5

μCT images at 6.7 μm resolution showing a bubble (white arrow) growing in a fibrous cap in the vicinity of μCalcs (arrow heads). (A) Dark area corresponds to air, gray to soft tissue and bright areas are calcifications. (B) Images corresponding to highlighted area in panel A, (C-D) sequence of images 67 μm apart from panel B (Scale bar is 250 μm).

Figure 6

High resolution μCT images of human coronary atheroma with μCalcs embedded in the fibrous cap proper. Panel A shows images scanned at 6.7-μm resolution. B was scanned at 2.1-μm resolution. Multiple μCalcs in the cap are visible in panel B magnified view, previously undetected in panel A. Magnified view of panels A and B show the difference between what appears to be a single μCalc at 6.7-μm and μCalc clusters when viewed at 2.1-μm resolution. Scale bar = 200 μm. (Reproduced with permission from Kelly-Arnold et al., Proc Natl Acad Sci U S A).

Figure 7

A) 3D FEA results of stress concentration factor calculated for the area between two particles located along the tensile axis in a fibrous cap. Stress concentration factor rises exponentially when the distance between the two spherical μCalcs decreases. Results are compared with previous 2D FEA reported in Maldonado et al. . B and C show FEA results for particles with initial h/D=0.3 oriented along and transverse the tensile axis respectively. (Reproduced with permission from Kelly-Arnold et al., Proc Natl Acad Sci U S A).

Figure 8

Ratio h/D for 193 pairs of μCalcs embedded in fibrous caps where h/D < 2, and the corresponding stress concentration factor when embedded in a fibrous cap along the tensile axis. Lines indicate mean ± SD. (Reproduced with permission from Kelly-Arnold et al., Proc Natl Acad Sci U S A).

Figure 9

TEM and histology based FEA. A) TEM image of aggregated calcifying matrix vesicles forming μCalcs in a mouse atheroma. B) Image of a μCalc embedded in a human fibrous cap, obtained from non-decalcified histology, stained von Kossa. C) and D) Stress distribution at the interface of the μCalcs in A and B respectively, assuming they are embedded in fibrous caps under tension. Numbers show calculated stress concentration factor at the poles. (Reproduced with permission from Kelly-Arnold et al., Proc Natl Acad Sci U S A).