doi: 10.1161/01.ATV.0000194157.26665.e6
© 2006 American Heart Association, Inc.
Letters to the Editor |
High Plasma Levels of Osteopontin in Patients With Restenosis After Percutaneous Coronary Intervention
National Defense Medical College, Saitama, Japan
To the Editor:
High levels of osteopontin (OPN) mRNA and proteins were reported in atherosclerotic plaques.1,2 Recently, we reported plasma OPN levels to be high in patients with coronary artery disease (CAD) and to correlate with the severity of CAD.3 However, no association between plasma OPN levels and restenosis after percutaneous coronary intervention (PCI) has yet been demonstrated.
We measured plasma OPN levels in 90 patients with CAD undergoing elective coronary angiography for suspected restenosis. They had undergone PCI 0.6±0.4 years ago, of whom 52 (58%) had been treated with bare metal stents. OPN levels were also measured in 60 age- and gender-matched CAD patients with no history of PCI. Patients with acute coronary syndrome were excluded. Our study was approved by institutional ethics committee. After informed consent was obtained, fasting blood samples were taken. Plasma OPN levels were measured by ELISA (Human OPN assay kit; IBL), which measures total concentration of phosphorylated and nonphosphorylated forms of OPN. CAD was defined as at least one coronary artery having >50% luminar diameter stenosis. Restenosis was defined as >50% luminar diameter stenosis in the segment treated by PCI. Differences between 2 groups were evaluated by unpaired t test for parametric variables, by Mann-Whitney U test for nonparametric variables, and by 
2 test for categorical variables. A probability value <0.05 was considered significant.
Of the 90 CAD patients with a history of PCI, 42 had restenosis. Compared with 48 CAD patients without restenosis, 42 with restenosis tended to have a higher rate of diabetes and a lower rate of smoking (Table). Among 3 groups, there was no difference in age, gender, or risk factors, except for total cholesterol levels. Plasma OPN levels were higher in CAD patients with restenosis than in those without restenosis and those with no history of PCI (P<0.01; Figure). CAD patients with restenosis more often had OPN level >600 ng/mL than those without restenosis and those with no history of PCI (38% versus 15% and 18%, P<0.05). OPN levels did not correlate with hsCRP, HbA1c, or fasting glucose levels. Clinical variables (age, gender, hypertension, hyperlipidemia, diabetes, smoking, stent, and hsCRP and OPN levels) were entered into multivariate logistic regression model. In addition to diabetes and smoking, OPN levels were independently associated with restenosis. Odds ratio for the presence of restenosis was 1.7 (95%CI=1.2 to 2.5; P<0.01) for a 100 ng/mL increase in OPN levels.
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Restenosis after angioplasty is caused by negative arterial remodeling and neointimal proliferation, whereas in-stent restenosis is caused mainly by neointimal proliferation.4 In vitro, OPN promotes the migration and proliferation of smooth muscle cells.2 Increased OPN mRNA was shown in neointimal smooth muscle cells after arterial injury in animal models.1 We generated OPN-overexpressing transgenic mice and demonstrated markedly increased neointimal formation after arterial injury.5 Liaw et al6 showed anti-osteopontin antibody treatment to reduce neointimal formation after injury in rat arteries. In humans, high levels of OPN mRNA and proteins were reported in atherectomy specimens from restenotic lesions.7 Panda et al2 showed plasma OPN levels in 13 patients undergoing coronary atherectomy to be elevated after atherectomy, and they remained high for at least 4 weeks. We showed plasma OPN levels to be higher in patients with than without restenosis and to be an independent factor for restenosis. OPN may play a role in the development of restenosis associated with neointimal proliferation.
Diabetes is a well-known clinical predictor of restenosis. In our study, diabetes was also a factor for restenosis. High glucose increases OPN mRNA in smooth muscle cells.8 Increased OPN expression was shown in diabetic arteries.9 Diabetes may thus facilitate restenosis via increased OPN production. However, OPN levels were a factor for restenosis independent of diabetes. Diabetes and increased OPN production may synergistically facilitate restenosis.
Our study was preliminary, because we did not measure OPN levels before PCI. Further study in a prospective manner is needed to elucidate the predictive value of plasma OPN levels before PCI for the development of restenosis. Moreover, we could not determine the main source of plasma OPN, because we did not measure OPN levels in coronary sinus.
Thus, high plasma levels of OPN in patients with a history of PCI were associated with the presence of restenosis, suggesting that OPN may play a role in the development of restenosis after PCI.
References
1. Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest. 1993; 92: 1686–1696.[Medline] [Order article via Infotrieve]
2. Panda D, Kundu GC, Lee BI, Peri A, Fohl D, Chackalaparampil I, Mukherjee BB, Li XD, Mukherjee DC, Seides S, Rosenberg J, Stark K, Mukherjee AB. Potential roles of osteopontin and 
vß3 integrin in the development of coronary artery restenosis after angioplasty. Proc Natl Acad Sci U S A. 1997; 94: 9308–9313.
3. Ohmori R, Momiyama Y, Taniguchi H, Takahashi R, Kusuhara M, Nakamura H, Ohsuzu F. Plasma osteopontin levels are associated with the presence and extent of coronary artery disease. Atherosclerosis. 2003; 170: 333–337.[CrossRef][Medline] [Order article via Infotrieve]
4. Schwartz RS, Henry TD. Pathophysiology of coronary artery restenosis. Rev Cardiovasc Med. 2003; 3: S4–S9.
5. Isoda K, Nishikawa K, Kamezawa Y, Yoshida M, Kusuhara M, Moroi M, Tada N, Ohsuzu F. Osteopontin plays an important role in the development of medial thickening and neointimal formation. Circ Res. 2002; 91: 77–82.
6. Liaw L, Lombardi DM, Almeida MM, Schwartz SM, deBlois D, Giachelli CM. Neutralizing antibodies directed against osteopontin inhibit rat carotid neointimal thickening after endothelial denudation. Arterioscler Thromb Vasc Biol. 1997; 17: 188–193.
7. O’Brien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz SM, Giachelli CM. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb. 1994; 14: 1648–1656.
8. Takemoto M, Yokote K, Yamazaki M, Ridall AL, Butler WT, Matsumoto T, Tamura K, Saito Y. Enhanced expression of osteopontin by high glucose in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1999; 258: 722–726.[CrossRef][Medline] [Order article via Infotrieve]
9. Takemoto M, Yokote K, Nishimura M, Shigematsu T, Hasegawa T, Kon S, Uede T, Matsumoto T, Saito Y, Mori S. Enhanced expression of osteopontin in human diabetic artery and analysis of its functional role in accelerated atherogenesis. Arterioscler Thromb Vasc Biol. 2000; 20: 624–628.
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