Injury or infection can disrupt normal endothelial function and initiate formation of atherosclerotic lesions known as
fatty streaks. Fatty streaks typically consist of macrophages and T cells embedded in a thin layer of lipids on the arterial wall.
2-5 Macrophages engulf lipids, becoming activated foam cells that release an array of chemoattractant molecules, cytokines, and growth factors. More lymphocytes are attracted to the lesion and, in turn, add to the pool of effector molecules that expand and perpetuate the inflammatory response. As this cycle is repeated, the plaque develops a fatty core covered by a fibrous matrix that stabilizes the structure.
3
The frequent presence of fatty streaks in young children is consistent with the chronic nature of atherosclerotic progression. Although the possible events that can initiate fatty streak formation remain controversial, LDL-C, modified by oxidation, glycation, and association with proteoglycans and immune complexes, can become trapped in the arterial wall, injuring the endothelium and vascular smooth muscle.
6-10 Once trapped, LDL-C particles become progressively more oxidized, form lipid peroxides, and facilitate accumulation of cholesterol esters.
3 Also, modified LDL-C is chemotactic for circulating monocytes and stimulates the proliferation of macrophages already in the lesion.
3 Inflammatory mediators increase the binding of LDL-C to endothelial cells and vascular smooth muscle cells that have migrated into the lesion.
11 As the plaque becomes thicker, the arterial wall responds by “remodeling,” that is, gradually dilating to maintain the diameter of the vessel lumen. Eventually, macrophages may be stimulated to release metalloproteinases that degrade the fibrous cap and render the plaque vulnerable to rupture.
12,13
Although several types of plaque can result in serious coronary events, retrospective analyses have demonstrated that 70% of all fatal acute myocardial infarctions and sudden coronary deaths are attributable to plaque rupture
14 or plaque erosion
15 (
Figure 1). This observation is not surprising because plaque destabilization is often accompanied by release of prothrombotic factors.
3 However, a recently developed consensus document emphasizes that all types of atherosclerotic plaques can result in coronary events and sudden death.
14 Vulnerable plaques are defined as thrombosis-prone or at risk of rapid progression and exhibit some combination of the following: active inflammation, thinning cap with a large lipid core, endothelial denudation with superficial platelet aggregation, fissures, or greater than 90% stenosis. The authors further conclude that the thrombotic status of the blood and the electrical instability of the myocardium are important to the ultimate outcome for the patient.
16
Although some of these criteria can be visualized with noninvasive procedures such as magnetic resonance imaging or computer-enhanced tomography, none is easily used for routine screening purposes. Thus, the ATP III risk factor assessment based on a 10-year cardiovascular risk remains the best tool to identify patients at high risk.
1