Abstract
The response to arterial wall injury is an inflammatory process, which over time becomes
integral to the development of atherosclerosis and subsequent plaque instability.
However, the underlying injurious agent, critical to this process, has not received
much attention. In this review, a model of plaque rupture is hypothesized with two
stages of inflammatory activity. In stage I (cholesterol crystal-induced cell injury
and apoptosis), intracellular cholesterol crystals induce foam cell apoptosis, setting
up a vicious cycle by signaling more macrophages, resulting in accumulation of extra
cellular lipids. This local inflammation eventually leads to the formation of a semi-liquid,
lipid-rich necrotic core of a vulnerable plaque. In stage II (cholesterol crystal-induced
arterial wall injury), the saturated lipid core is now primed for crystallization,
which can manifest as a clinical syndrome with a systemic inflammation response. Cholesterol
crystallization is the trigger that causes core expansion, leading to intimal injury.
We recently demonstrated that when cholesterol crystallizes from a liquid to a solid
state, it undergoes volume expansion, which can tear the plaque cap. This observation
of cholesterol crystals perforating the cap and intimal surface was made in the plaques
of patients who died with acute coronary syndrome. We have also demonstrated that
several agents (ie, statins, aspirin, and ethanol) can dissolve cholesterol crystals
and may be exerting their immediate benefits by this direct mechanism. Also, because
recent studies have demonstrated that high-sensitivity C-reactive protein may be a
reliable marker in selecting patients for statin therapy, it could reflect the presence
of intimal injury by cholesterol crystals. This was demonstrated in an atherosclerotic
rabbit model. Therefore, we propose that cholesterol crystallization could help explain
in part both local and systemic inflammation associated with atherosclerosis.
Keywords
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Article info
Publication history
Published online: March 17, 2010
Accepted:
March 5,
2010
Received:
January 28,
2010
Identification
Copyright
© 2010 National Lipid Association. Published by Elsevier Inc. All rights reserved.
