Atherosclerosis

Atherosclerosis refers to the underlying progression in arterial dysfunction and remodeling that restricts blood flow to vessels in the peripheral vasculature.1 Taken from the Greek, athero (gruel or paste) and sclerosis (hardness), atherosclerosis describes the buildup of lipid-laden fatty deposits within the vessel wall that is often called atheroma or atherosclerotic plaques. As illustrated in Figure 1, temporal morphological changes accompany the progression of disease. In its early stages, atherosclerosis causes significant changes to the vessel wall with the accumulation of cholesterol and scar tissue. The lesion is preceded by a fatty streak in the intima below the endothelium, composed of lipid-enriched macrophages and T cells. These fatty streaks are usually symptomatically silent, are frequently observed in teenagers and young adults, and may either disappear or progress to more advanced disease. As the lesion develops, it is enriched in cholesterol-laden foam cells, becomes calcified, and hardens. In later stages, the developing lesion induces a thickening of the vessel wall due to smooth-muscle cell (SMC) migration and proliferation above the foam cells, accompanied by the formation of a tough, fibrous cap over the lipid-laden core. The resulting plaque may be stable for long periods or may be unstable and prone to rupture.

Two types of vessel wall remodeling have been observed using intravascular ultrasound (IVUS) imaging techniques: (1) positive remodeling that largely maintains the lumen diameter as the lesion grows inward through the vessel wall and the external elastic membrane area expands; and (2) negative remodeling, where the external elastic membrane area contracts and lesion growth narrows the luminal diameter and restricts blood flow.2 Historically, lesions that impeded blood flow were thought to be the most dangerous as the progressive narrowing restricted blood flow and oxygen supply to the heart, eventually leading to heart attack and myocardial infarct (MI). However, recent angiographic studies indicate that in many cases the most dangerous lesions appear at sites where blood flow is not severely restricted. The latest studies indicate that plaque activation and rupture rather than stenosis are considered to be the primary underlying events preceding ischemia and infarct.

Figure 1 The initiation and progression of atherosclerosis in arterial vessels starting from LDL modification and oxidation leading to lipid retention, monocyte recruitment and inflammation, then macrophage activation and foam cell development ending in plaque rupture and thrombus formation. (Reprinted with permission by Keith Kasnot.)

rupture

Figure 1 The initiation and progression of atherosclerosis in arterial vessels starting from LDL modification and oxidation leading to lipid retention, monocyte recruitment and inflammation, then macrophage activation and foam cell development ending in plaque rupture and thrombus formation. (Reprinted with permission by Keith Kasnot.)

Atheromas that either impede or do not impede blood flow are subject to rupture. Typically, the fibrous cap becomes weakened as inflammatory mediators from within the lesion are secreted and degrade the overlying extracellular matrix. The cap then develops cracks that rupture the lesion, exposing tissue factor from below the vessel wall that induces the extrinsic coagulation cascade locally at the site and quickly leads to thrombus formation. The resulting loss of oxygen supply to the heart produces cellular and tissue injury and ultimately culminates in chest pain (angina), heart attack, and/or MI. The disrupted flow to the carotid artery or in microvessels within the brain produces stroke (see 6.10 Stroke/Traumatic Brain and Spinal Cord Injuries). The underlying atherosclerotic process develops slowly and asymptomatically in early adulthood, where clinical signs and symptoms are typically not observed until after age 45 in males and later after menopause in females. Both MI and stroke frequently occur without any prior warning, require emergency treatment and hospitalization, and have immediate life-threatening consequences.

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