Reassessing the Mechanisms of Acute Coronary Syndromes

Abstract

The mechanisms that underlie superficial erosion, a cause of coronary thrombosis distinct from plaque rupture, have garnered recent interest. In an era of improved control of traditional risk factors, such as LDL (low-density lipoprotein), plaque erosion may assume greater clinical importance. Plaques complicated by erosion tend to be matrix-rich, lipid-poor, and usually lack prominent macrophage collections, unlike plaques that rupture, which characteristically have thin fibrous caps, large lipid pools, and abundant foam cells. Thrombi that complicate superficial erosion seem more platelet-rich than the fibrinous clots precipitated by plaque rupture. The pathogenesis of plaque rupture probably does not pertain to superficial erosion, a process heretofore little understood mechanistically. We review here data that support a substantial shift in the mechanisms of the thrombotic complications of atherosclerosis. We further consider pathophysiologic processes recently implicated in the mechanisms of erosion. Multiple processes likely predispose plaques to superficial erosion, including experiencing disturbed flow, basement membrane breakdown, endothelial cell death, and detachment potentiated by innate immune activation mediated through pattern-recognition receptors and endothelial-to-mesenchymal transition. Monocytes/macrophages predominate in the pathogenesis of plaque rupture and consequent thrombosis, but polymorphonuclear leukocytes likely promote endothelial damage during superficial erosion. The formation of neutrophil extracellular traps probably perpetuates and propagates intimal injury and potentiates thrombosis due to superficial erosion. These considerations have profound clinical implications. Acute coronary syndromes because of erosion may not require immediate invasive therapy. Understanding the biological bases of erosion points to novel therapies for acute coronary syndrome caused by erosion. Future research should probe further the mechanisms of superficial erosion, and develop point-of-care tests to distinguish acute coronary syndromes provoked by erosion versus rupture that may direct more precision management. Future clinical investigations should evaluate intervening on the targets that have emerged from experimental studies and the management strategies that they inform.

Keywords: acute coronary syndrome; atherosclerosis; macrophages; monocytes; neutrophils; thrombosis.

Figure 1.. Comparison of the characteristics of human atheromata complicated by thrombosis due to plaque rupture (top) or superficial erosion (bottom).

The column on the left highlights some of the characteristics demonstrated by analyses of human coronary arterial lesions that have undergone thrombosis by these two diverse mechanisms. NETs = neutrophil extracellular traps (Illustration Credit: Ben Smith).

Figure 2.. Some possible mechanisms of endothelial cell desquamation associated with superficial erosion and arterial thrombosis.

The left side of this diagram shows proteolysis affected by enzymes such as the matrix metalloproteinases that can degrade the integrins on the basal surface of endothelial cells represented by the α and β, or the constituents of the basement membrane to which the endothelial cells adhere through integrin/matrix binding. Basement membranes contain about 40% of Type IV collagen, a substrate of matrix metalloproteinase-2 (MMP-2) a Type IV collagenase that undergoes activation by the membrane associated proteinase MMP-14. The right side of this diagram depicts endothelial cell death by apoptosis or other mechanisms that can lead to sloughing of the luminal endothelial cells affording access of the blood and its formed elements including platelets to the subjacent intimal layers. (Illustration Credit: Ben Smith).

Figure 3.. A hypothetical timeline of events that can promote thrombosis due to superficial erosion.

This hypothetical timeline depicts a possible sequence of events (from left to right) that can lead to thrombosis due to superficial erosion. Endothelial cells can undergo low-grade smoldering activation as depicted by assuming a less squamous and more columnar morphology. Candidate stimuli include TLR2 ligands such as hyaluronan fragments among other innate immune activators including damage-associated molecular patters (DAMPs.) Endothelial cells with severed tethers to the basement membrane or those that have undergone various forms of cell death as depicted in Figure 2 can desquamate allowing access of platelets and neutrophils to subendothelial structures. Activation of platelets by contact with collagen and triggering of NETosis in the localized granulocytes can initiate and propagate the formation of a platelet-rich thrombus depicted on the right-hand side of this diagram showing activated platelets that can bridge through fibrin binding and adhere to collagen through glycoprotein VI. The red spiral structures in the platelet-rich thrombus depict DNA strands derived from NETs, decorated with thrombogenic and pro-inflammatory mediators as shown in Figure 4. (Illustration Credit: Ben Smith).

Figure 4.. Formation of neutrophil extracellular traps and selected mediators associated with NETs that can participate in local arterial thrombosis.

NETs can bear proteins contained in neutrophil granules released during neutrophil activation. These proteins include those derived from azurophilic or primary granules including myeloperoxidase, Cathepsin G, neutrophil elastase (NE), and proteinase 3 (PR3), among other hydrolytic enzymes including a series of phospholipases that can generate biologically active lipid mediators of inflammation. NETs can also acquire proteins from extra-neutrophilic sources including tissue factor (TF) that can activate Factor VII and through activation of Factor Xa lead to local thrombin generation that produce fibrin locally. NE and other extracellular matrix-degrading proteins such as neutrophil collagenase and gelatinases can further degrade the basement membrane and underlying extracellular matrix macromolecules including basement membrane constituents and fibrillar collagens. (Elastin fragments may promote chemoattraction of further granulocytes.) Myeloperoxidase generates the highly pro-oxidant species hypochlorous acid (HOCl). Pro- interleukin-1-alpha (IL-1α) derived from neutrophils can bind to the DNA strands that comprise NETs. NETs can activate pro-inflammatory functions of endothelial cells through stimulation by IL-1α. The neutrophil serine proteinase Cathepsin G can enhance the local activity of IL-1α by cleaving the pro- form to produce the more active mature form of this pro-inflammatory cytokine. (Illustration Credit: Ben Smith).

Figure 5.. Endothelial-mesenchymal transition may contribute to superficial erosion.

The left-hand part of this diagram depicts a resting endothelial monolayer tightly adherent to the underlying basement membrane. A number of junctional proteins including those depicted here contribute to the barrier function of an intact resting endothelial monolayer. These resting endothelial cells have a squamous morphology with apical-basal polarization. In response to signals such as transforming growth factor beta (TGF-β), withdrawal or loss of function of fibroblast growth factor, or augmented vascular endothelial growth factor (VEGF) signaling, the cells express higher levels of matrix metalloproteinases (MMPs) 2 and 9, enzymes capable of degrading basement membrane constituents. These and other proteinases can disturb the integrin molecules localized on the basal aspect of the endothelial cells that tether them to the basement membrane, as depicted in Figure 2. These stimulated cells lose their squamous morphology and apical-basal polarization that characterize the resting endothelial cell, and acquire front to rear polarization. The endothelial cells can slough due to the interrupted binding to the basement membrane. Local permeability of the endothelial monolayer increases due to dissolution of the junctional proteins that determine the barrier function of the intimal interface with blood. The loss of endothelial cell coverage permits contact with subjacent structures in the intima that may promote platelet activation as depicted on the right side of this diagram. The cells that have acquired the mesenchymal character can invade and penetrate into the underlying atherosclerotic plaque in the intima. (Illustration Credit: Ben Smith).