doi: 10.1161/01.ATV.0000229701.42828.73
© 2006 American Heart Association, Inc.
Letters to the Editor |
Effect of Atorvastatin on Plasma Osteopontin Levels in Patients With Hypercholesterolemia
National Defense Medical College, Saitama, Japan
To the Editor
High levels of osteopontin (OPN) mRNA and proteins were reported in atherosclerotic plaques.1,2 OPN-transgenic mice developed marked atherosclerosis.3 We reported plasma OPN levels to be high in patients with coronary artery disease (CAD) and to correlate with the severity of CAD.4 We also reported high plasma levels of OPN in patients with restenosis.5 These suggest that OPN plays a role in the development of atherosclerosis. In vitro, Takemoto et al6 demonstrated statins to reduce OPN mRNA in cultured aortic smooth muscle cells and upregulated OPN mRNA in aorta of diabetic rats.
We investigated the effects of 20 mg/d versus 5 mg/d atorvastatin on plasma OPN levels in 40 hypercholesterolemic patients without any history of cardiovascular disease. Our study was approved by institutional ethics committee. If patients were taking statins, these were discontinued. After 4-week washout period, fasting blood samples were taken after informed consent was obtained. If LDL-cholesterol >150 mg/dL, patients were randomized to either dose. Repeat blood sampling was scheduled after 6-month treatment. OPN levels were measured by ELISA (Human OPN assay kit, IBL). LDL-cholesterol and high sensitivity C-reactive protein (hsCRP) levels were measured by direct enzymatic method and by BNII nephelometer (Dade Behring). Differences between 2 groups were evaluated by unpaired t test for continuous variables, by Mann–Whitney U test for nonparametric variables (hsCRP), and by 
2 test for categorical variables. Differences between baseline and 6-month were evaluated by paired t test for parametric variables and by Wilcoxon rank test for hsCRP. Correlations between changes in OPN levels and LDL-cholesterol or other levels were evaluated by Pearson correlation coefficient. A probability value <0.05 was considered significant.
Of 50 patients randomized, 6 withdrew of their own accord, and 4 had adverse events. After 6 months, blood samples were taken in 18 patients in 20-mg dose and 22 in 5-mg dose group. At baseline, risk factors and OPN levels did not differ between 2 groups (Table 1). OPN levels did not correlate with LDL-cholesterol or hsCRP levels. After 6 months (Table 2), 20-mg and 5-mg doses reduced LDL-cholesterol levels (–47% and –35%). The degree of LDL-cholesterol reduction was greater in 20-mg than in 5-mg dose group. The 20-mg and 5-mg doses reduced hsCRP levels (–44% and –44%), but the degree of hsCRP reduction was similar in 2 groups. The 20-mg dose reduced OPN levels (–19%, P<0.05), whereas 5-mg dose did not (–7%). Notably, the degree of OPN reduction correlated with that of hsCRP reduction (r=0.51) (Figure). No correlation was found between the degrees of OPN or hsCRP reduction and LDL-cholesterol reduction.
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Several large clinical trials showed beneficial effects of statins for cardiovascular diseases.7 Clinical benefits observed with statin appeared to be greater than what might be expected from lipid-altering effects alone. In vitro studies showed some non-lipid pleiotropic effects of statins on atherosclerosis.7 In vivo, plasma hsCRP levels decreased after 8-week cerivastatin treatment.8 Serum matrix metalloproteinase (MMP)-9 levels decreased after 6-month pravastatin treatment.9 In vitro, statins reduced OPN mRNA in cultured aortic smooth muscle cells and abnormally upregulated OPN mRNA in aorta of diabetic rats.6 However, no report has shown the effect of statins on plasma OPN levels. Our study first demonstrated 6-month atorvastatin treatment to reduce plasma OPN levels. Although both 20-mg and 5-mg atorvastatin markedly reduced LDL-cholesterol and hsCRP levels, 20-mg dose reduced OPN levels. The degree of OPN reduction appeared to be dose-dependent, but difference between 2 doses did not reach statistical significance, probably because of a small sample size. The degree of OPN reduction did not correlate with LDL-C reduction, as reported in hsCRP.8 Interestingly, the degree of OPN reduction correlated with that of hsCRP reduction. The reduction in OPN production may be one of pleiotropic effects of statins and may contribute to beneficial effects of statins for cardiovascular diseases.
Our study was on a small number of Japanese patients. 20-mg dose was used as high-dose of atorvastatin, because it is the maximal approved dose in Japan. Our results may not be applicable to other ethnicities. Blood samples were taken at baseline and 6-month. To validate the effect of atorvastatin on OPN levels and to provide any clinical end point correlations, further study with follow-up is needed. OPN is synthesized in atherosclerotic plaques as well as mineralized tissues. However, we could not determine the main source of plasma OPN.
Thus, 20-mg atorvastatin treatment reduced plasma OPN levels in hypercholesterolemic patients. The reduction in OPN production may be one of pleiotropic effects of statins.
Acknowledgments
Disclosures
None.
References
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- Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001; 21: 1712–1719.
[Abstract/Free Full Text] - Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hyprecholesterolemia. Circulation. 2001; 103: 1191–1193.
[Abstract/Free Full Text] - Kalela A, Laaksonen R, Lehtimaki T, Koivu TA, Hoyhtya M, Janatuinen T, Pollanen P, Vesalainen R, Saikku P, Knuuit J, Nikkari ST. Effect of pravastatin in mildly hypercholesterolemic young men on serum matrix metalloproteinases. Am J Cardiol. 2001; 88: 173–175.[CrossRef][Medline] [Order article via Infotrieve]
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