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Vulnerable Plaque
Iftikhar J. Kullo, MD;
William D. Edwards, MD; and
Robert S. Schwartz, MD
7 September 1999 | Volume 131 Issue 5 | Pages 393-394
IN RESPONSE:
Krishnaswamy and colleagues outline several mechanisms by which mast cells might contribute to plaque inflammation and rupture. Further work is needed to establish a direct role for mast cells in plaque instability. The hypothesis that plaque behavior could be favorably altered by preventing mast-cell degranulation or by inhibiting mast-cell proteases is intriguing but as yet unproven. Drs. Doherty and McMillen point out the several proatherogenic properties of endothelin-1. The work by Zeiher and coworkers (1) suggests that endothelin-1 is involved in the pathogenesis of acute coronary syndromes. However, evidence for endothelin-1 as an important determinant of plaque vulnerability and rupture is yet to come. With the introduction of endothelin-1 antagonists, an opportunity exists to further explore the role of endothelin-1 in the behavior of atherosclerotic plaques. If endothelin-1 antagonists do reduce coronary events, a central role for endothelin in promoting plaque instability could then be postulated.
Dr. de' Clari proposes that colchicine may have a stabilizing effect on atherosclerotic plaques. Colchicine binds tubulin and disrupts the microtubular system in granulocytes and other motile cells. This leads to a decrease in chemotaxis, metabolic and phagocytic activity, and resulting anti-inflammatory effects. Because of these properties, the drug has been tested for antiatherogenic effects in animal models. The results have been inconsistent. In cholesterol-fed rabbits, colchicine decreased atheroma formation (2), but it had no effect in a swine model of aortic atherosclerosis (3). Although effects on macrophage cytokine production and metalloproteinase activation (4) may be beneficial, the inhibition of fibrosis by colchicine (5) could be detrimental to plaque stability. At present, the therapeutic potential of colchicine, if any, in atherosclerosis is unclear; further studies are needed.
The issues raised by the respondents highlight the need for animal models of plaque rupture in which these hypotheses could be tested.
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Author and Article Information
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Mayo Clinic and Mayo Foundation; Rochester, MN 55905 (Kullo)
Mayo Clinic and Mayo Foundation; Rochester, MN 55905 (Edwards)
Mayo Clinic and Mayo Foundation; Rochester, MN 55905 (Schwartz)
1. Zeiher AM, Goebel H, Schachinger V, Ihling C. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. A clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina Circulation. 1995;91:941-7.[Abstract/Free Full Text]
2. Hollander W, Kramsch DM, Franzblau C, Paddock J, Colombo MA. Suppression of atheromatous fibrous plaque formation by antiproliferative and anti-inflammatory drugs Circ Res. 1974;34-35(Suppl 1):131-41.
3. Lee WM, Morrison ES, Scott RF, Lee KT, Kroms M. Effects of methyl prednisolone and colchicine on the development of aortic atherosclerosis in swine Atherosclerosis. 1976;25:213-24.[Medline]
4. Wesley RB, Meng X, Godin D, Galis ZS. Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro Arterioscler Thromb Vasc Biol. 1998;18:432-40.[Abstract/Free Full Text]
5. Entzian P, Schlaak M, Seitzer U, Bufe A, Acil Y, Zabel P. Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis Lung. 1997;175:41-51.[Medline]
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Reviews
Vulnerable Plaque: Pathobiology and Clinical Implications
Iftikhar J. Kullo, William D. Edwards, AND Robert S. Schwartz
- Annals 1998 129: 1050-1060.
[ABSTRACT][Full Text]
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