The role of low endothelial shear stress in the conversion of atherosclerotic lesions from stable to unstable plaque

Abstract

Purpose of review: Local hemodynamic factors are major determinants of the natural history of individual atherosclerotic plaque progression in coronary arteries. The purpose of this review is to summarize the role of low endothelial shear stress (ESS) in the transition of early, stable plaques to high-risk atherosclerotic lesions.

Recent findings: Low ESS regulates multiple pathways within the atherosclerotic lesion, resulting in intense vascular inflammation, progressive lipid accumulation, and formation and expansion of a necrotic core. Upregulation of matrix-degrading proteases promotes thinning of the fibrous cap, severe internal elastic lamina fragmentation, and extracellular matrix remodeling. In the setting of plaque-induced changes of the local ESS, coronary regions persistently exposed to very low ESS develop excessive expansive remodeling, which further exacerbates the proinflammatory low ESS stimulus. Recent studies suggest that the effect of recognized cardioprotective medications may be mediated by attenuation of the proinflammatory effect of the low ESS environment in which a plaque develops.

Summary: Low ESS determines the severity of vascular inflammation, the status of the extracellular matrix, and the nature of wall remodeling, all of which synergistically promote the transition of stable lesions to thin cap fibroatheromata that may rupture with subsequent formation of an occlusive thrombus and result in an acute coronary syndrome.

Figure 1.. Atherosclerotic plaque heterogeneity within a human coronary artery.

A. Cross section of a human coronary artery just distal to a bifurcation. The atherosclerotic plaque to the left (circumflex branch) is fibrotic and partly calcified, whereas the plaque to the right (marginal branch) is lipid-rich with a non-occluding thrombus superimposed. B. Higher magnification of the plaque-thrombus interface reveals that the fibrous cap over the lipid-rich core is extremely thin, inflamed, and ruptured with a real defect in the cap. Trichrome stain, staining collagen blue and thrombus red. Reprinted from [1], with permission from Elsevier.

Figure 2.. Role of low ESS in fibrous cap attenuation and the formation of thin cap fibroatheromata.

Digital photomicrographs of oil red O-stained (A and C) and CD45-stained (B and D) fibroatheroma from a porcine coronary artery, with a thin fibrous cap inflamed at its shoulders (small black arrowheads). L indicates lumen; M, media; A, adventitia; F, fibrous cap; N, necrotic core; and C, calcification. C and D are magnifications of the black box in A and B, respectively. The necrotic core is extended into the media through the disrupted IEL (A and B; large black arrowheads). L indicated lumen; M, media; A, adventitia; F, fibrous cap; N, necrotic core; C, calcification. E. Association of minimum cap thickness with the magnitude of baseline ESS; dashed lines represent 95% CI for the regression line. The arteries were snap frozen and not pressure fixed immediately after harvesting; the actual lumen dimensions can therefore not be accurately assessed, due to tissue shrinkage at −80^oC. Reprinted from [13].

Figure 3.. Association of the magnitude of low ESS with the severity of high-risk plaque characteristics

Association of ESS magnitude at baseline (week 23) with the severity of high-risk plaque characteristics at follow-up (week 30), in a diabetic, hyperlipidemic model of atherosclerosis. *: p<0.05 for each characteristic in very low ESS vs. the respective characteristic in moderate or high ESS; p=0.13 for inflammation in very low ESS vs. low ESS. Reprinted from [13].

Figure 4.. Colocalization of heparanase with lipids and inflammatory cells in a coronary region of low ESS.

Figure from a porcine coronary artery section, showing a thin cap fibroatheroma that developed in a coronary region of preceding low ESS. Note that immunostaining for heparanase (HPA, A) co-localizes with staining oil-red O (lipids, B), and immunostaining with CD45 (inflammatory cells, C). Satining with picrosirius red (PR, D) indicates collagen and reveals the thin fibrous cap overlying the necrotic core.

Figure 5.. Effect of persistently low ESS in the formation of expansively remodeled atherosclerotic plaque.

Representative example of a serially profiled porcine coronary artery. A. Two-dimensional maps show the ESS distribution along the artery length at five cosecutive time points of in-vivo vascular profiling at weeks 4, 11, 16, 23, and 36 after the induction of diabetes and hyperlipidemia. In each map, the horizontal axis denotes the artery circumference (°) and the vertical axis the artery length (mm). The red rectangle denotes a proximal segment which is peristently exposed to low ESS, throughout its natural history. B. Two-dimensional maps showing the plaque thickness, external elastic lamina radius and lumen radius distribution along the artery length at final week 36; in each map, the horizontal axis denotes the artery circumference (°) and the vertical axis the artery length (mm). Red rectangles include the same proximal segmet, as in figure A. This arterial segment displays maximal plaque thickness, and also significant expansion of the vessel wall, as indicated by the orange-red color in the corresponding maps. Note that even the lumen exhibits maximal expansion, despite the formation of significant plaque, indicating excessive expansive remodeling, i.e. an exagerrated, aneurysm-like form of arterial remodeling that not only preserves normal lumen dimensions, but actually causes lumen increase under the effect of sufficiently low ESS.

Figure 6.. Association between longitudinal atherosclerotic plaque morphology and spatial distribution of local ESS.

A. Top: histologic appearance of a human carotid artery plaque stained with Elastic–van Gieson. Horizontal arrow indicates direction of blood flow. Box on the left indicates proximal (upstream) shoulder of plaque; box on the right represents the distal (downstream) shoulder. Middle: boxed area of proximal shoulder stained with anti-CD68 (macrophages; MΦ) and anti–a-actin (smooth muscle cell, SMC). Bottom: boxed area of distal shoulder stained with anti-CD68 (macrophages; MΦ) and anti–a-actin (smooth muscle cell, SMC). Note the abundance of macrophages in the upstream shoulder, and of smooth muscle cells in the downstream shoulder, respectively. Modified from [62]. B. Differential spatial distribution of ESS along a lumen protruding plaque. Arrows pepresent velocity vectors. The upstream shoulder is exposed to low ESS. Local ESS is elevated in the throat, and low / oscillatory in the downstream shoulder of the developing plaque. These local ESS conditions promote the formation of a vulnerable, plaque-prone phenotype, indicated by the red rectangle, upstream of the lesion, and additional growth, indicated by the dashed line, downstream of the plaque. NC: necrotic core.

Figure 7.. Role of low ESS in the formation of rupture-prone plaque.

Schematic presentation of the mechanisms whereby low local ESS promotes the conversion of an early fibroatheroma to a thin cap fibroatheroma, major precursor lesion of rupture-mediated thrombosis.