doi: 10.1161/01.ATV.0000149672.83911.5b
© 2004 American Heart Association, Inc.
Editorials |
Glimpse of the Secret Life of the Plaque
From the Department of Medicine and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Correspondence to Goran K. Hansson, Department of Medicine and Center for Molecular Medicine L8:03, Karolinska University Hospital, SE-17176 Stockholm, Sweden. E-mail Goran.Hansson{at}cmm.ki.se
For many years, atherosclerosis was thought to be a slow process of continuous growth of lesions. It was generally believed to be irreversible and to cause clinical symptoms when the sheer size of the plaque obstructed blood flow. This view has been completely changed during the last decade. Early studies of primates showed that whereas a high-cholesterol diet induced atherosclerotic lesions, a switch to low-fat diet led to regression of plaques within a few months.1 These findings revealed that the atherosclerotic process is much more dynamic than had previously been anticipated. When modern lipid-lowering drugs became available, patients with coronary heart disease were treated aggressively and their coronary circulation examined by repeated angiographies.2 Again, some plaques were found to regress on treatment. However, clinical studies showed more remarkable effects on clinical events than on the degree of stenosis,2 suggesting that regression therapy acts to modify the composition of the plaque as well as reducing its size.
See page 2307
Analysis in experimental models have confirmed and extended these conclusions. When hypercholesterolemic rabbits were switched to a lipid-lowering diet, the composition of the lesions changed rapidly into a more stable phenotype.3,4 Smooth muscle cells accumulated and collagen increased whereas inflammation waned and signs of proteolytic and prothrombotic activity were reduced. All of these phenomena reflect the cellular dynamics of the atherosclerotic plaque, where metabolic changes impact on cell accumulation, differentiation, and gene expression. Whereas hyperlipidemic conditions promote the formation of large, vulnerable plaques with activated immune cells, intense inflammation, proteolysis, and prothrombotic conditions, lipid lowering can reverse the process. Inflammation cools down, proteases and prothrombotic factors disappear, and the smooth muscle cells form a stable cap stabilized by collagen bundles.
The careful characterization of the regression process in experimental animals has been of great importance for understanding and developing therapeutic principles in man. However, the possibilities to follow the regression—or progression—of individual lesions in patients are still very limited. Angiography remains a golden standard but does not really tell us anything about the composition of the lesions. Indeed, angiography portrays what is not there by depicting the lumen rather than the artery wall. Among other imaging modalities, ultrasonography has undergone a rapid development and can now be used to measure the size of lesions. It is even possible to identify lipid core regions, particularly when intravascular ultrasound (IVUS) is used. However, this technology is technically demanding and invasive, and conventional ultrasonography is hampered by limited resolution. The same is still true for MRI, although rapid progress is taking place and high resolution with chemical selectivity may become a reality within a few years. Unfortunately, even such high-resolution methods cannot provide information about the molecular dynamics that characterize atherosclerotic events. Instead, the report by Torzewski et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology5 may open up new possibilities for monitoring regression of disease by such a molecular approach.
The new study uses radiolabeled antibodies to detect uptake of oxidized molecules in lesions. Such antibodies accumulate in lesions of progressive disease but do not label lesions undergoing regression. Although the new study used ex vivo detection of 125I-labeled antibodies, the authors have previously demonstrated that such antibodies can be detected also by gamma camera technology.6 This suggests that it may be possible to develop scintigraphic technology for monitoring progression/regression of atherosclerotic plaques in patients.
The molecular marker for disease activity used in the new study reflects oxidative activity. Lipid peroxidation generates malondialdehyde, which binds to and may crosslink 
-amino groups of lysines in polypeptide chains. Malondialdehyde adducts are formed on the apolipoprotein B moiety during oxidation of LDL and leads to rapid uptake through scavenger receptors on macrophages and other cells.7 The MDA2 antibody used by Torzewski et al recognizes a small epitope consisting of malondialdehyde-lysine; it is common in oxidized LDL but can also occur in other proteins exposed to products of lipid peroxidation. In vivo uptake of MDA2 therefore probably presents an integrated view of oxidative activity and accumulation of oxidized LDL. This, in turn, reflects the presence of activated macrophages, which makes MDA2 an attractive tool for identifying plaques with high inflammatory activity. Indeed, MDA2-positive lesions were found to contain more macrophages, fewer smooth muscle cells, and less collagen than MDA2-negative ones. This clearly suggests that MDA2 detects vulnerable but not stable lesions.
The finding that antibodies reacting with oxidized LDL relatively selectively recognize active vulnerable lesions suggests an important role for LDL oxidation in disease development. It adds to strong evidence for LDL oxidation being a trigger for intracellular cholesterol accumulation,8 initiating autoimmune reactions by breaking T-cell tolerance9 and ligating natural antibodies,10 and by promoting endothelial cell activation.11 Several clinical studies have shown that circulating levels of oxidized LDL12 as well as titers of antibodies to such particles13,14 correlate to progression of coronary heart disease and other manifestations of atherosclerosis. It will now be important to determine whether the total level of LDL oxidation, or merely its accumulation in plaques, reflects progressive atherosclerotic disease. In other words, is there a future role for MDA2 and similar antibodies in immunochemical serum assays of risk markers as well as in scintigraphic imaging of lesions?
There is now solid documentation, from the present study and several previous ones, that oxidation-specific antibodies accumulate to a greater extent in active vulnerable plaques than in regressing stable ones. The present study suggests that imaging of antibody accumulation can be used to identify vulnerable plaques and to monitor the effect of stabilizing therapy. Based on these exciting observations, it is now time to test the new tools and principles for in vivo imaging, first in live animals and later, hopefully, in patients.
References
1. Armstrong ML, Heistad DD, Megan MB, Lopez JA, Harrison DG. Reversibility of atherosclerosis. Cardiovasc Clin. 1990; 20: 113–126.[Medline] [Order article via Infotrieve]
2. Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993; 87: 1781–1791.
3. Aikawa M, Rabkin E, Okada Y, Voglic SJ, Clinton SK, Brinckerhoff CE, Sukhova GK, Libby P. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation. 1998; 97: 2433–2444.
4. Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, Fallon JT, Libby P. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation. 1999; 100: 1215–1222.
5. Torzewski M, Shaw PX, Han K-R, Shortal B, Lackner KJ, Witztum JL, Palinski W, Tsimikas S. Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization. Arterioscler Thromb Vasc Biol. 2004; 24: 2307–2312.
6. Tsimikas S, Palinski W, Halpern SE, Yeung DW, Curtiss LK, Witztum JL. Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol. 1999; 6: 41–53.[CrossRef][Medline] [Order article via Infotrieve]
7. Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci U S A. 1980; 77: 2214–2218.
8. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983; 52: 223–161.[CrossRef][Medline] [Order article via Infotrieve]
9. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized LDL. Proc Natl Acad Sci U S A. 1995; 92: 3893–3897.
10. Binder CJ, Horkko S, Dewan A, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med. 2003; 9: 736–743.[CrossRef][Medline] [Order article via Infotrieve]
11. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997; 386: 73–77.[CrossRef][Medline] [Order article via Infotrieve]
12. Holvoet P, Perez G, Zhao Z, Brouwers E, Bernar H, Collen D. Malondialdehyde-modified low density lipoprotein in patients with atherosclerotic disease. J Clin Invest. 1995; 95: 2611–2619.
13. Salonen JT, Yla-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssonen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992; 339: 883–887.[CrossRef][Medline] [Order article via Infotrieve]
14. Bergmark C, Wu R, de Faire U, Lefvert AK, Swedenborg J. Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL. Arterioscler Thromb Vasc Biol. 1995; 15: 441–445.
Related Article:
Arterioscler Thromb Vasc Biol 2004 24: 2307-2312.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||