Endothelial dysfunction is a critical feature in the onset of atherogenesis. The endothelium is in direct contact with, and reacts to, various mechanical and molecular stimuli to maintain hemostasis, inflammation, and vascular tone. Endothelial injury may be caused by several factors (listed in Table 95.1), particularly in regions of the vessel subject to low shear stress and altered blood flow.⁷ These insults lead to a rise in angiotensin II, reduced nitric oxide (NO) production, and increase in the expression of superoxide dismutase, which compromise the integrity of the endothelial barrier. The reduced NO concentration is unable to inhibit the nuclear factor kappa-light chain enhancer of activated B cells (NF-kB) pathway, which leads to endothelial cell activation. Activated cells increase expression of cytokines (monocyte chemoattractant protein-1 and interleukin-8), monocyte adherence proteins (P-selectin, vascular cell adhesion protein-1, intercellular adhesion molecule-1), and proinflammatory receptors (toll-like receptor-2). The loss of endothelial integrity allows direct contact between blood constituents and the arterial intima—the site of atheroma development—and concomitant activation of endothelial cells results in a proinflammatory and prothrombotic environment (Figure 95.1).

Once endothelial damage has occurred, retention and accumulation of cholesterol-loaded atherogenic lipoproteins (ie, low-density lipoproteins [LDL], remnants of very low-density lipoproteins [VLDLs] and chylomicrons, and lipoprotein (a) [Lp(a)]) in the subendothelial space occur. Their accumulation in the intima further promotes endothelial dysfunction and triggers inflammation, which is the pivotal step for the development of fatty streak and the progression of atheroma. Both native and modified lipoproteins (ie, through oxidation and glycation) can trigger an immune response that participates in atherogenesis.⁸ Inflammatory signals induce endothelium activation, expression of adhesion molecules, and chemoattractants that promote recruitment of monocytes into the subendothelial space, as well as other immune cells, including regulatory T cells, T helper dendritic cells (Th-1), and mast cells.

Once in the intima, monocytes are activated to become macrophages that internalize and degrade the proatherogenic lipoproteins retained in the subendothelial space. This amplifies and perpetuates the expression of inflammatory mediators. Following lipoprotein phagocytosis, free cholesterol is released and transported to the endoplasmic reticulum to be esterified and stored as cholesteryl ester in lipid droplets in the cytoplasm, thereby forming foam cells. In an attempt to reduce the formation and progression of foam cells, free cholesterol is cleared from macrophage cytoplasm by three major metabolic pathways—ATP-binding cassette subfamily G member 1,
scavenger receptor class B type I, and aqueous diffusion—and captured by native, cholesterol-poor high-density lipoproteins (HDLs) in the reverse cholesterol transport process.

Inflammatory mediators released by macrophages (such as platelet-derived growth factor) stimulate the migration and proliferation of smooth muscle cells from the media to the intima layer. This is a crucial stage in the development of atheroma, as the presence of smooth muscle cells envisages plaque progression and a lower likelihood of plaque regression. Smooth muscle cells confer plaque stability, as they are the primary source of elastin, proteoglycans, and collagen, components of the extracellular matrix that make up the fibrous cap and protect against its rupture. HDL particles reduce the inflammatory response via mechanisms not related to cholesterol efflux such as antioxidative effects, decreasing expression of endothelial adhesion molecules, and reducing thrombosis.

The continuous accumulation of atherogenic lipoproteins in the intima, their modification and phagocytosis by both macrophages and metaplastic smooth muscle cells results in plaque volume growth. Finally, the progressive increase in intracellular free cholesterol levels, especially in the endoplasmic reticulum, may trigger apoptosis.

As the volume of cells in the atheromatous plaque increases, the vessel undergoes positive remodeling because of an increase in the internal elastic lamina area, which attenuates obstruction of the vessel lumen (ie, increasing the external diameter of the vessel to allow preservation of the arterial flow). This effect—termed the Glagov phenomenon—is the result of accumulation of macrophages that express matrix metalloproteinases (MMPs) like MMP-2, MMP-9, and MMP-13 that digest extracellular matrix proteins. Meanwhile, apoptosis of macrophages leads to their clearance from the plaque interior.
However, with atheroma progression, the process of clearing dead cells and associated cellular debris (called efferocytosis) becomes dysfunctional, thereby accumulation of cellular debris and deposition of cholesterol crystals contribute to the formation of the necrotic core. Smooth muscle cell migration and proliferation continue, building additional cell layers that result in a thick fibrous cap that covers the necrotic core. This cover protects the plaque against rupture and its consequent core exposure to prothrombotic factors.

Another factor involved in plaque stabilization is the development of vascular calcifications. This is an active process that resembles the process of bone mineralization. During plaque progression, some regions develop foci of calcium deposits, but this process is not uniform. Although microcalcifications in the fibrous cap may generate instability and predispose to plaque rupture initially, the evolution to extensive organized, structured calcifications may lead to lower risk of thrombotic events because of biomechanical stability.

Plaque vulnerability is the result of a continuous inflammatory insult associated with the development of the lipid core that increases the risk of plaque rupture, and it may develop in different stages of plaque progression. The progression of the necrotic core leads to the exposure of inflammatory and cytoplasmic oxidative components that cause necrosis of neighboring cells. This results in the release of oxidation products, cytokines, and inflammatory mediators that lead to degradation of extracellular matrix, reduction of collagen production, and death of smooth muscle cells. Moreover, the released metalloproteinases (such as MMP-3) promote the thinning of the fibrous cap, a fundamental alteration for atheroma complications. Such changes facilitate plaque rupture. The plaque content (ie, greater lipid area, concentration of cholesterol esters, and number of macrophages) correlates with the propensity for plaque rupture.

Once the plaque surface is breached, there is exposure of the necrotic core to procoagulant factors and blood platelets. As dysfunctional endothelium has reduced capacity to prevent clot formation and promote fibrinolysis, the plaque disruption triggers thrombus formation and, consequently, acute cardiovascular events.

In patients taking lipid-lowering therapies, the progression of plaque vulnerability may have different pathophysiologic features, such as plaque erosion and ulceration rather than plaque rupture. In advanced stages of atherosclerosis, apoptosis and consequent desquamation of endothelial cells occur, configuring areas of plaque erosion that, in contrast with plaque ruptures, contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps.⁹ The result is the organization of a less occlusive “white” thrombus with plaque erosion, which is more likely to be associated with the clinical presentation of a non-ST-segment elevation myocardial infarction.