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Prevention of Plaque Rupture: A New Paradigm of Therapy

James S. Forrester, MD
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From Cedars-Sinai Medical Center, Los Angeles, California.

Requests for Single Reprints: James S. Forrester, MD, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.

Ann Intern Med. 2002;137(10):823-833. doi:10.7326/0003-4819-137-10-200211190-00012
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Acute coronary syndromes—unstable angina, myocardial infarction, and sudden cardiac death—are caused by acute disruption of an unstable coronary atheroma. Unstable plaques have three histologic characteristics: a large lipid core, many inflammatory cells, and a thin fibrous cap. Because the unstable plaque is not necessarily obstructive, it may cause no symptoms before rupture. The cellular processes that lead to the characteristic histologic features of unstable plaque have recently been identified. This new understanding of the cell biology of plaque instability suggests new therapeutic strategies: passivation of the endothelium, reduction of low-density lipoprotein (LDL) in the vessel wall by decreasing serum LDL levels or accelerating reverse cholesterol transport, inhibition of LDL oxidation, inhibition of inflammatory cytokine expression, and inhibition of thrombus formation. Although the morbidity and mortality resulting from acute coronary disease have been reduced by more than 50% over the past 30 years, it is reasonable to anticipate further reductions of similar magnitude in the decade ahead.


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Figure 1.
The angioscopic appearance of stable and unstable atheroma. Left.Middle.Right.

The typical smooth surface of a stable atheroma in a patient with stable angina. The disrupted intimal surface of an atheroma in a patient with unstable angina. A thrombus on the surface of a disrupted atheroma in a patient with acute myocardial infarction.

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Figure 2.
The steps in atheroma destabilization.LDL

Activated endothelial cells express adhesion molecules, which attract leukocytes that enter the blood vessel wall. Low-density lipoprotein ( ) in the vessel wall is oxidized and taken up by macrophages. The activated cells in the vessel wall express cytokines, which maintain the inflammatory process. Proteases digest the fibrous cap, and smooth-muscle cells undergo apoptosis, leading to rupture of the fibrous cap.

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Figure 3.
The biological processes that induce plaque destabilization and the therapeutic strategies that inhibit these processes.

If the processes are relatively independent, the therapies may have an additive effect. LDL = low-density lipoprotein.

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