Plaque instability is now acknowledged to be the major cause of unstable angina, myocardial infarction, and sudden cardiac death. Unstable lesions (that are not necessarily severely stenotic) with a large lipid core, many inflammatory cells, and a thin fibrous cap are associated with acute coronary syndromes. The role of cytokines in contributing to plaque instability also is being elucidated. Forrester describes the process of plaque instability and provides clinical strategies for reducing the incidence of acute coronary syndromes.
Plaque instability begins with endothelial activation caused by both the classic cardiac risk factors (elevated cholesterol levels, smoking, and hypertension) and more recently identified factors (homocysteine, immune complexes, and some infectious agents). Activated endothelium causes local adherence of blood cells that can enter the blood vessel wall. As cells enter the endothelium, low-density lipoprotein (LDL) cholesterol also enters and is oxidized and taken up by macrophages. This lipid and macrophage core is the largest segment of an unstable plaque.
All cell types in the vessel wall are activated, as occurs in other chronic inflammatory processes, and cytokines and proteolytic enzymes are expressed. These enzymes cause collagen degradation, resulting in thinning of the fibrous cap of the atheroma, while the cytokines decrease smooth muscle cell function and cause apoptosis (cell death). Systemic inflammatory factors also contribute to plaque instability, as demonstrated by increased C-reactive protein and fibrinogen levels in patients with acute coronary syndrome.
Although reduction of lipids has been a standard method of reducing the risk of coronary heart disease, this new understanding of unstable plaques (see accompanying table) provides additional methods of risk reduction.
Reducing endothelial activation: angiotensin II is in dynamic balance with nitric oxide. When the balance is in favor of angiotensin II, endothelial activation begins, potentially resulting in plaque destabilization. Angiotensin-converting enzyme inhibitors can reduce macrophage infiltration and cell adhesion, resulting in decreased atherosclerosis. Angiotensin-II receptor blockers seem to have the same effect, although fewer clinical studies have been completed. Fish oils may elevate high-density lipoprotein (HDL) cholesterol levels, decrease very-low-density lipoprotein cholesterol levels, and reduce atherogenesis.
Reducing LDL cholesterol levels: lipid reduction reduces macrophage content in the vascular endothelium. The exact goal for lipid reduction is still being studied; the concept of aggressive lipid lowering to an LDL level of less than 80 mg per dL (2.05 mmol per L) is being evaluated. Statins also may have anti-inflammatory actions and decrease plaque macrophage and cholesterol content.
Accelerating reverse LDL cholesterol transport: raising HDL cholesterol and lowering triglyceride levels with the use of niacin or fibrates can increase the rate of LDL cholesterol reverse transport, thus lowering cholesterol in the plaque and decreasing the cardiac event rate.
Inhibiting the oxidative state: vitamin E and beta-carotene have antioxidant properties and may be useful, but the clinical data are contradictory. Folic acid seems useful in decreasing homocysteine levels, but any method of reduction has not yet been shown to reduce adverse cardiac events.
Inhibiting inflammatory cytokines. The increase of inflammatory cytokines in persons with acute coronary syndromes and the recently demonstrated association with Chlamydia pneumoniae suggest that antibiotics may have some use, but the efficacy of antibiotics in primary or secondary prevention of adverse cardiac events has not been demonstrated. Studies have demonstrated that the anti-inflammatory effect of aspirin can be helpful in patients with plaque instability by decreasing levels of interleukin-6, C-reactive protein, and macrophage colony-stimulating factor.
Inhibiting thrombosis: aspirin and clopidogrel seem useful because of their ability to inhibit platelet aggregation and reduce thrombus formation.
The authors conclude that trials are needed to determine what combinations of therapies added to diet and LDL cholesterol lowering will provide clinically useful outcomes. It remains to be determined if the effects of using all of these treatments will be additive and will result in a decrease in adverse coronary events.