Inflammation plays a key role in the subclinical phases of atherosclerosis. The early phases involve recruitment of inflammatory cells. To initiate formation of an atheromatous plaque, something must recruit mononuclear phagocytes to the cells of the endothelial surface. Normally, mononuclear phagocytes resist prolonged contact these cells.

Researchers now know there are a series of molecules that allow adhesion of white blood cells to the endothelial cells. One such molecule that has been of particular interest is vascular cell adhesion molecule-1 (VCAM-1). Endothelial cells do not normally express VCAM-1, but proinflammatory mediators such as cytokines can induce production of this molecule.

Mice that have a mutation influencing VCAM-1 function have impaired atheroma initiation, providing genetic evidence that this molecule is indeed important for early atherogenesis.

After a white blood cell has adhered to the endothelium, directed migration into the artery wall can occur. Chemokines, which are chemoattractant cytokines, cause this directed migration.

One chemokine in particular is monocyte chemoattractant protein-1 (MCP-1). It has produced great interest among researchers because it is a potent chemoattractant for both monocytes and lymphocytes. Endothelial and smooth muscle cells in the area where lesions are going to form can produce this chemokine. Dr. Libby and colleagues have shown that mice with a defect in MCP-1 have impaired atherogenesis.

Adhesion and directed migration set the stage for development of the atherosclerotic lesion itself. The phenotype of the white blood cell changes from that of the usual blood monocyte to that of a tissue macrophage. It also expresses scavenger receptors that allow it to engulf modified lipoprotein particles.

Researchers believe macrophage colony stimulating factor (M-CSF) is an important mediator of the inflammatory process. Endothelial cells can produce this potent monocyte activator, which localizes in human and experimental atheromatous plaques.

These inflammatory processes can help explain much of the benefit of current effective therapies for atherosclerosis such as lipid reduction with diet or statins.

Angiographically monitored statin studies show a large disparity between the degree of improvement in lumen size and the patient's clinical benefit. Although lipid lowering increases the lumen only slightly, the clinical benefit is substantial. Thus, the functional state of the plaque may be as important as the size or degree of luminal encroachment.

Studies of cholesterol-fed rabbits suggest a mechanism through which lipid lowering could influence the risk that a particular lesion may cause an acute coronary syndrome.

In one experiment, researchers created lesions in rabbits with balloon injury and high cholesterol feeding. Some rabbits stayed on the diet for 16 months, while others shifted to a low cholesterol diet, allowing their hypercholesterolemia to subside.

Baseline evaluation of the lesions revealed that smooth muscle cells formed a fibrous cap bordering the lumen and at the base of the plaque. In the lipid core of the lesions were abundant macrophages. The rabbit plaques also expressed the enzyme collagenase (MMP-1), which researchers believe can weaken plaque and precipitate a thrombotic complication.

Returning rabbits to a normal diet seemed to have an anti-inflammatory effect. There were many fewer macrophages. There was a decrease in collagenase and a reciprocal increase in intimal collagen, suggesting a more stable plaque. In addition, there was a decrease in tissue factor, suggesting lower thrombogenicity.

Researchers have extended these studies to illustrate an decrease in oxidative stress as cholesterol decreases. Oxidized low-density lipoprotein cholesterol levels also decrease, as do levels of VCAM-1, the molecule important for recruiting monocytes. There is also a decrease in endothelial nitric oxide synthase, the enzyme that makes nitric oxide.

Now, preliminary observations suggest dietary cholesterol lowering in this animal model yields fewer microvessels in the plaque. This subject will require more study. However, evidence to date strongly suggests that inflammation is an integral part of the atherogenic process and that lipid lowering is an anti-inflammatory therapy.