Journal
JOURNAL OF CLINICAL LIPIDOLOGY
Volume 14, Issue 5, Pages 619-630Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacl.2020.07.003
Keywords
Lipids and cholesterol; Atherosclerosis; Acute coronary syndromes
Categories
Funding
- Michigan State University
- Jean P. Schultz Biomedical Research Endowment
- Department of Medicine, College of Human Medicine, East Lansing, MI
- Edward W. Sparrow Hospital, Lansing, MI
- Merck pharmaceutical research grant, Kenilworth, NJ
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Reducing the residual risk of cardiovascular (CV) events in patients with atherosclerosis continues to be a challenge. Thus, understanding how cholesterol spontaneously self assembles into meta-stable structures that evolve into flat plate cholesterol crystals (CCs) in atherosclerotic plaque, and why they fundamentally change the nature of the disease provides a paradigm for the development of additional therapies. Specifically, flat plate CCs that form within lysosomes of macrophages may become large enough to disrupt lysosomal membranes leading to the release of cathepsin B and CCs fragments directly into the cytosol. In the cytosol, the surface of flat plate CCs can be recognized by complosome that together with cathepsin B may trigger pyrin domain-containing inflammasome. In addition, flat plate CCs in the cytosol may trigger caspase 8 initiating apoptosis. In the interstitial space, the surface of flat plate CCs can be recognized by complement and receptors on proinflammatory cells, and larger fragments can induce frustrated phagocytosis that together perpetuate inflammatory injury. In addition, rapid transition of metastable CCs into large flat plate CCs within lipid rich plaques can lead to traumatic injury by expansion of the plaque's necrotic core causing plaque disruption or rupture that may precipitate further inflammation. Other crystalloids in plaque including monosodium urate and calcium phosphate crystals can augment these processes. Thus, therapies that further limit the deposition of cholesterol in the vascular bed, slow the formation of flat plate CCs and inhibit crystal-induced inflammation may lead to further reduce CV risk in patients with established CV disease. (C) 2020 National Lipid Association. All rights reserved.
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