Biology and pathology of atherosclerosis

Atherosclerosis is a systemic inflammatory disease. The initial steps of atherogenesis involve cholesterol accumulation in the intima that is thought to mediate recruitment of inflammatory leucocytes, followed by development of a fibro-fatty plaque comprising a lipid core and macrophages that ultimately evolve into lipid-rich foam cells.

Initiation of atheroma

Lipoprotein particles accumulate in the arterial intima soon after initiation of hypercholesterolaemia and undergo oxidative and other chemical modifications that can confer proinflammatory properties such as induction of adhesion molecules that mediate leucocyte adherence.

During the initial phases of atherogenesis, endothelial cells express molecules such as vascular cell-adhesion molecule-1 (VCAM-1) in a patchy distribution that reflects the ultimate location of arterial plaques.

Oxidized low-density lipoprotein (LDL) in the arterial intima can mediate other proinflammatory effects, such as (1) stimulating endothelial and smooth muscle cells to produce potent chemokines, which can encourage adherent leucocytes to migrate through the endothelium into the arterial intima to initiate plaque formation; (2) activating leucocytes after their recruitment into the plaque, leading to the production of further inflammatory molecules, such as cytokines, and small molecules, such as biologically active eicosanoids.

Antiatherogenic processes oppose this potent cocktail of proatherogenic events, including reverse cholesterol transport—whereby high-density lipoproteins (HDL) unload cholesterol from lipid-laden plaque macrophages and carry it away from the arterial wall for breakdown and disposal.

Evolution of atheroma

Inflammatory monocytes and T cells enter the arterial wall along a chemokine gradient, forming the earliest microscopic lesion of atheroma. The recruited monocytes mature into macrophages, promoting expression of the scavenger receptors that permit the unregulated uptake of cholesterol-laden, modified, lipoprotein particles and leading them to become foam cells, which form a small fatty streak that progresses gradually to become an atheromatous plaque.

As the fatty streak matures, the smooth muscle cells produce extracellular matrix and the fibrous components that produce the characteristic structure of a subendothelial fibrous cap overlying a lipid-rich core and deeper islands of smooth muscle cells and macrophages. Events within the atheromatous plaque are complex: endothelial cells form internal, immature, leaky haemorrhage-prone microvessels that provide a new site for entry into the lesion of inflammatory monocytes that perpetuate the atherosclerotic process; they also present a potential site for the intraplaque bleeding associated with plaque progression. Some plaques show deposition of calcium over time in a process similar to bone mineralization.

Atheromatous plaques are unpredictable—atheroma progresses through very gradual cellular accumulation, as described above, punctuated by crises that promote lesion development. These crises may occur when a plaque erodes or ruptures, exposing its thrombogenic core and causing sudden, partial luminal thrombosis.

Acute coronary syndromes

Acute coronary syndromes follow sudden thrombotic events related to the exposure of circulating platelets to thrombogenic components of the plaque via either superficial erosions or rupture of the plaque’s fibrous cap. Careful anatomopathological study has given rise to the concept of the ‘vulnerable’ plaque—an intact plaque similar to those present beneath the site of a fatal coronary thrombosis that is characterized by a thin fibrous cap, a relative paucity of smooth muscle cells, and an abundance of inflammatory cells, particularly macrophages. Plaques that rupture are not necessarily those that cause high-grade stenoses: intravascular ultrasound studies and autopsy data show that many individuals have multiple high-risk or vulnerable plaques as well as ruptured plaques, causing symptomatic or fatal acute coronary syndromes.