Evolution of C-Reactive Protein as a Cardiac Risk Factor

Paula J. D'Amore, PhD, D(ABMLI)

Disclosures

Lab Med. 2005;36(4):234-238. 

In This Article

Atherosclerosis and Inflammation

Inflammation is defined as a response to injury from infectious, physical, or chemical agents. It is now widely accepted that inflammation plays a major role in the development and progression of atherosclerosis. The initial injury that occurs in atherosclerosis is damage to the endothelial cells lining the blood vessels. Some of the factors leading to the injury include increased levels of oxidized low density lipoproteins (LDL-C) found in dyslipidemia, free radicals formed by cigarette smoking, possible infectious agents, and the shearing stress placed on endothelial cells due to hypertension.[6] The endothelial cell wall injury triggers a cascade of events and the secretion of mediators that modulates the inflammatory response. The homeostatic properties of the surface of the endothelial cell become procoagulant allowing leukocytes and platelets to adhere. Nuclear factor kappa- B is released[7] and initiates the transcription of cytokines involved in inflammation including tumor necrosis factor-α (TNF-α), chemokines such as monocyte chemoattractant protein-1 (MCP-1) and the vascular cell adhesion molecule-1 (VCAM-1). Monocyte chemoattractant protein-1 attracts circulating monocytes to the site of injury, and through binding to VCAM-1, monocytes adhere to the endothelial cell wall. The monocytes are then able to migrate across the endothelial barrier into the intima layer and differentiate into macrophages. They phagocytosize the increased amount of lipoproteins from the LDLs and transform into foam cells. These cells secrete pro-inflammatory molecules such as interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-α; all of which can contribute to additional leukocyte accumulation and induce smooth muscle proliferation and migration from the medial layer into the intima. The arterial wall begins to thicken as more LDLs are taken up by macrophages and an atheroma is formed. An atheroma is a core of lipids and necrotic cellular debris resulting from dying foam cells. The smooth muscle cells produce collagen which forms a fibrous cap over the atheroma. In order to compensate for the growth of the atheroma, the vessel dilates and allows for continuous blood flow. Eventually, the size of the atherosclerotic plague encroaches on the lumen of the blood vessel causing a reduction in blood flow. Plague develops most commonly in areas of increased turbulence where direction of blood flow changes at branches and bifurcations. The continuous elaboration of the proteolytic enzyme, matrix-metalloproteinases (MMP), by the macrophages under the fibrous cap initiates a breakdown of the collagen. As a result, the cap weakens and eventually ruptures (Figure 1). The atheroma and its thrombotic material is exposed and leads to the formation of a thrombus and ensuing emboli. This is the precipitating event that can lead to a myocardial infarction.

Figure 1.

Rupture of fibrous plaque in atherosclerosis. The atherosclerotic plaque consisting of the atheroma and the fibrous cap ruptures due to the weakening of the cap through the elaboration of the MMP by the macrophages under the cap. This can result in the formation of a thrombus and the eventual occlusion of the blood vessel. Figure used with permission from the New England Journal of Medicine (originally published Jan. 14, 1999).

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