doi: 10.1161/CIRCULATIONAHA.105.606962
(Circulation. 2006;113:e782.)
© 2006 American Heart Association, Inc.
Correspondence |
Letter by Williams and Tabas Regarding Article "Atherosclerosis 2005: Recent Discoveries and Novel Hypotheses"
Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa
Columbia University, College of Physicians and Surgeons, New York, NY
Although the ideas put forth by Goldschmidt-Clermont et al1 are intriguing, we believe that their article underplays a large body of work, much of it from the past 2 decades, that has clarified how normal arteries become atherosclerotic.2–5 Low-density lipoprotein (LDL) is not mysteriously injurious. Instead, as experimentally demonstrated by Skålén et al,4 LDL causes harm only if it becomes retained, or trapped, within the arterial wall. Moreover, without LDL retention, atherosclerosis does not develop, even if other known risk factors are present. There are no known circumstances in humans or in animal models in which atherosclerosis is caused by stem cell defects, inflammation, senescence, or endothelial injury per se in the absence of unhealthy levels of LDL or related particles in plasma (meaning above a therapeutically attainable goal of ~70 mg/dL).2 Retained LDL provokes a series of responses in the arterial wall that accounts for all known features of this disease, including the development of the lipid-rich vulnerable plaque. The therapeutic implications of these hard-won insights are clear: We should lower unhealthy plasma levels of LDL and modify other conventional risk factors, and we should enhance "reverse" lipid transport out of plaques. Benefits from these approaches have been demonstrated in animal models and in humans.5 In contrast, clinical trials of antioxidants, antiinflammatory agents, and antibacterials have shown no benefits in this disease to date,5 and the potential utility of stem cells remains highly speculative. We agree with Goldschmidt-Clermont et al1 that there is a need for further study and therapeutic improvements,5 but it is important to emphasize that our field already has robust, proven remedies that are based on a well-tested understanding of the pathogenesis of this major killer.
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Acknowledgments |
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Sources of Funding
Dr Williams was supported by research grants NIH HL56984 and NIH HL73898. Dr Tabas was supported by research grant NIH HL56984.
Disclosures
Dr Williams is the inventor of a number of patents on the use of phospholipid liposomes to promote reverse lipid transport in vivo (now held by Pfizer). Dr Williams received honoraria as a member of the ARA Research Awards Committee, Pfizer. Dr Tabas received honoraria from Merck and Schering-Plough and is a consultant for Merck.
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References |
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 Top References |
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1. Goldschmidt-Clermont PJ, Creager MA, Losordo DW, Lam GKW, Wassef M, Dzau VJ. Atherosclerosis 2005: recent discoveries and novel hypotheses. Circulation. 2005; 112: 3348–3353.
2. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995; 15: 551–561.
3. Hurt-Camejo E, Olsson U, Wiklund O, Bondjers G, Camejo G. Cellular consequences of the association of apoB lipoproteins with proteoglycans: potential contribution to atherogenesis. Arterioscler Thromb Vasc Biol. 1997; 17: 1011–1017.
4. Skålén K, Gustafsson M, Rydberg EK, Hultén LM, Wiklund O, Innerarity TL, Borén J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750–754.[CrossRef][Medline] [Order article via Infotrieve]
5. Williams KJ, Tabas I. Lipoprotein retention and clues for atheroma regression. Arterioscler Thromb Vasc Biol. 2005; 25: 1536–1540.
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Circulation 2006 113: 2473.
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