Mechanisms of erosion of atherosclerotic plaques

Abstract

Purpose of review: The present review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis.

Recent findings: Human coronary artery atheroma that give rise to thrombosis because of erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs endothelial cell barrier function, impairs endothelial cell viability, recruits neutrophils, and provokes endothelial cells desquamation, NET formation, and thrombosis in a TLR2-dependent manner.

Summary: Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.

Figure 1

Distinct mechanisms can trigger coronary thrombosis due to superficial erosion vs. fibrous cap rupture. This figure portrays cross-sections of coronary arteries. The image on the left represents thrombosis due to erosion as a “white” mural thrombus overlying a lesion rich in extracellular matrix. Endothelial cell death and desquamation can uncover basement membrane collagen that might promote platelet-rich thrombi. Recruited polymorphonuclear leucocytes (PMN) could contribute to a second wave of thrombus amplification and propagation by forming NETs. We have conjectured that erosion associates more frequently with non-ST-segment elevation ACS (NSTEMI) than with ST-segment elevation myocardial infarction (STEMI). The right side of this illustration depicts thrombosis due to rupture of a thin fibrous cap. Such thrombi tend to share characteristics of a fibrin-rich ‘red’ clot. Tissue factor made by the many macrophages in such lesions can provoke clotting. Lesions prone to rupture may develop more outward “Glagovian” remodeling. (Adapted from Libby, P. Superficial erosion and the precision management of acute coronary syndromes: not one-size-fits-all.” Eur Heart J 2017:38(11): 801–803.)

Figure 2

DNA extruded by dying granulocytes form NETs visible as frond-like processes protruding into the lumen from the intimal surface of a representative human carotid plaque specimen with an erosion-associated structure. This merged immunofluorescent micrograph shows neutrophil elastase (green), citrullinated histone-4 (pink), and nuclei (blue.) (Adapted from Quillard, T., et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 36(22): 1394–1404.)

Figure 3

A “two-hit” schema of superficial erosion complicated by thrombosis. On the bottom, this diagram depicts a longitudinal section of an artery harboring a glycosaminoglycan-rich (darker brown) atheroma. The left side (1) highlights some of the candidate triggers for initiating chronic low-level endothelial damage, e.g. pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and other substances that can engage innate immune receptors on endothelial cells, e.g. TLR2. Hyaluronic acid, abundant in human plaques complicated by superficial erosion, may ligate TLR2. Several stimuli from the inflammatory cells in plaques as well as modified lipoproteins can promote endothelial cell apoptosis. Enzymes that degrade the extracellular matrix such as the matrix metalloproteinases can catabolize constituents of the basement membrane to which endothelial cells adhere. MMP-2, MMP-9, and MMP-14, enzymes found in plaques, can thus disturb the attachment of endothelial cells to the intima. The right side of this diagram (2) shows the amplification and propagation of local intimal damage and thrombosis after a patch of endothelial cells slough. Once an endothelial cell has detached (as shown by the endothelial cell with a pycnotic nucleus) the agonal endothelial cell can elaborate microparticles that contain the potent procoagulant tissue factor. Neutrophils adherent to the denuded area can degranulate and generate locally reactive oxygen species (e.g. hypochlorous acid, HOCI, a product of myeloperoxidase [MPO], and superoxide anion [O₂⁻], as well as the calgranulin family member MRP-8/14. This scheme posits the polymorphonuclear leukocytes as later arrivals on the scene at site of superficial erosion. Dying granulocytes extrude DNA and histones forming NETs. NETs form a nidus for thrombus growth and entrapment of other leukocytes and platelets, aggravating the local inflammatory response. Activated platelets release pro-inflammatory mediators (e.g. interleukin-6 and RANTES) and plasminogen activator inhibitor-1 (PAI-1), a blocker of fibrinolysis, that can increase the durability of clots. (Adapted from Quillard, T., et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 36(22): 1394–1404.)