Atherogenesis

Normal Arterial Wall

The normal artery consists of three distinctive layers: the intima, the innermost layer comprising a single layer of endothelial cells on the luminal surface; the media, a tube of vascular smooth muscle cells (VSMCs) and their extracellular matrix shown in the first image below; and the adventitia, the outer protective layer comprising loose connective tissue containing blood vessels and nerves which supply the artery itself.^1,2

The endothelial cells of the intima have a number of important functions; forming a non-thrombotic, non-adherent surface, acting as a semi-permeable membrane, synthesising and releasing chemical mediators, maintaining the basement membrane, and modifying lipoproteins as they cross into the artery wall.

The VSMCs of the media contract and relax to alter the lumen diameter of the vessel in response to a variety of circulating and local stimuli, regulating vascular tone, blood flow and blood pressure. This is effected through the production of a number of vasoactive substances including prostaglandins, endothelin and nitric oxide (NO).^1,2

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Historical Model of Atherogenesis

Originally it was thought that atherogenesis was a relatively simple process and revolved around the formation of atheromatous plaques within the intimal wall leading to eventual blockage of the artery. The gradual increase in size of the plaque was thought to encroach into the lumen of the artery, eventually causing a reduction in lumen size. The resulting reduction in blood flow was then thought to cause stable angina pectoris and rarely, myocardial infarction.³

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New Paradigm

More recently, atherogenesis has been revealed as a complex process and is preceded and accompanied by inflammation. The endothelium responds to damage by inducing a protective response, eventually leading to the formation of the atherosclerotic plaque. Over time, the plaque may grow or reduce in size, and may or may not encroach into the lumen of the artery. The clinical outcome often depends on the stability of the plaque.⁴ The less stable the plaque, the more susceptible it is to erosion or rupture. Both erosion and rupture can lead to thrombus formation on the site of the plaque and vessel occlusion, culminating in unstable angina or myocardial infarction.⁴ Treatment with statins, in addition to dietary and lifestyle changes, may result in diminished progression, or even regression of atherosclerotic plaques.

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References:
1. Ross R. N Engl J Med 1999;362:115–126.
2. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective. Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1-19.
3. Antischkow N. Beitr Path Anat Allg Path 1913;56:379–404.
4. Ross R. Nature 1993:362:801–809.

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