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Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:e121-e125
Published online before print May 11, 2006, doi: 10.1161/01.ATV.0000226544.93089.7f
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:e121.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Elevated Plasma Active Matrix Metalloproteinase-9 Level Is Associated With Coronary Artery In-Stent Restenosis

Gregory T. Jones; I. Patrick Kay; J.W. S. Chu; G.T. Wilkins; L.V. Phillips; M. McCormick; A.M. van Rij; M.J.A. Williams

From the Sections of Surgery (G.T.J., L.V.P., A.M.v.) and Medicine (I.P.K., J.W.S.C., G.T.W., M.M., M.J.A.W.), University of Otago, Dunedin, New Zealand.

Correspondence to Dr Gregory T. Jones, Vascular Research Group, Section of Surgery, University of Otago, PO Box 913, Dunedin, New Zealand. E-mail greg.jones{at}otago.ac.nz


*    Abstract
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 *Abstract
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Objective— This study aimed to determine whether the plasma levels of matrix metalloproteinase-9 (MMP-9) or tissue inhibitor of metalloproteinases-1 (TIMP-1) were altered in patients with a history of symptomatic in-stent restenosis (ISR).

Methods and Results— A group of 158 patients with a history of ISR were compared with 128 symptom-free patients. Plasma samples and a detailed risk factor history were collected. Plasma samples were analyzed for pro–MMP-9 and latent MMP-9 and active MMP-9, latent MMP-3, and TIMP-1. Several variables were associated with ISR, including index coronary disease extent and severity (number of diseased vessels and American College of Cardiology/American Heart Association lesion classification), number, diameter, and total length of stent(s) inserted, and plasma high-density lipoprotein cholesterol. Plasma active MMP-9 (odds ratio, 1.96; 95% CI, 1.43 to 2.69) showed independent risk association with ISR. Patients with multiple sites of ISR had significantly higher levels of active MMP-9 compared with patients with only a single ISR lesion or no ISR.

Conclusion— Plasma active MMP-9 levels may be a useful independent predictor of bare metal stent ISR.

This study aimed to determine whether plasma MMP-9 or TIMP-1 levels were elevated in patients with a history of (bare metal) in-stent restenosis. Plasma active MMP-9 was independently associated with ISR with a stratified risk association with the number of sites of ISR. Future studies should therefore prospectively evaluate plasma levels of active MMP-9 as a possible independent predictor of ISR.


Key Words: plasma • MMP-9 • TIMP-1 • restenosis


*    Introduction
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 *Introduction
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Vascular connective tissue remodeling is a well-recognized ubiquitous process that occurs after percutaneous coronary interventions including intracoronary stent placement.1 Mechanical injury has been shown to induce collagenase and stromelysin gene expression in cultured smooth muscle2 and an increase in gelatinase activity after balloon catheter injury to the rat carotid.3,4 Overexpression of the gelatinase matrix metalloproteinase-9 (MMP-9) has been shown to enhance smooth muscle cell (SMC) migration within in vitro assays. Moreover, the levels of various MMPs appear to be associated with postinterventional vascular remodeling in human blood vessels.5–10 Such in vitro and in vivo findings suggest that increased levels of MMPs in coronary arteries undergoing percutaneous intervention may be associated with vascular remodeling and restenosis by promoting migration of vascular SMCs.

In this study, the circulating plasma levels of pro–MMP-9, latent MMP-9 and active MMP-9, latent MMP-3, and tissue inhibitor of metalloproteinases-1 (TIMP-1) were investigated in patients who had previously undergone bare metal coronary stent placement. Patients were subdivided into those who developed symptomatic, angiographically proven, in-stent restenosis (ISR) and those who were (angina) symptom-free for >1 year after their stent placement.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
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Subjects
Patients with coronary bare-metal stent placements were recruited retrospectively from the Dunedin Hospital Cardiology Clinical database. A group of 158 consecutive patients with a history of symptomatic, angiographically proven, ISR (coronary artery disease [CAD] with ISR) were compared with a consecutive series of 128 patients who were angina-free for >1 year after their stent placement (CAD with stent). The CAD with ISR group included patients who had undergone repeat percutaneous intervention or coronary artery bypass surgery and were then free of symptoms and cardiovascular events for ≥6 months. The majority (97.2%) of patients were of white ethnicity, the remainder being New Zealand Mâori (2.1%) or Asian (0.7%). Coronary angiograms in all patients were analyzed by an experienced cardiologist, with the extent of CAD expressed as the number of vessel territories (left anterior descending, left circumflex, and right coronary arteries) with ≥1 stenoses of ≥50% of the vessel normal reference diameter using visual assessment of lesion severity. CAD extent was expressed as single-, double-, or triple-vessel CAD. The American College of Cardiology/American Heart Association (ACC/AHA) classification11 was used to evaluate the morphology of coronary lesions at the index coronary angiogram. Follow-up angiography was analyzed in the restenosis group with the definition of restenosis being diameter stenosis ≥50% of the vessel reference diameter by visual assessment at the site of the lesion treated with the stent observed in ≥1 multiple projections. The single most severe view was used to categorize the pattern of restenosis as proposed by Mehran et al12 for classification of in-stent restenotic lesions.

A detailed record of each individual’s current medications, body mass index (BMI), waist-to-hip ratio (WHR), and risk factor history, including previous history of hypertension, hyperlipidemia, diabetes, other vascular diseases, and smoking history, was collected. One smoking pack year was defined as 20 cigarettes (1 pack) per day for 1 year. All subjects gave written informed consent before being recruited into this study.

Sample Analysis
Plasma samples were analyzed for lipoprotein(a) (Lp(a)) concentration (sandwich ELISA), high-sensitivity C-reactive protein (hs-CRP; Roche, Tina-quant high sensitivity [latex] assay), and lipid profiles (enzymatic-colorimetric method; Roche).

Endogenous plasma MMP-3 and MMP-9 was assessed in heparin plasma sample using the Biotrak Activity Assay System (product RPN 2639 and RPN 2634; Amersham Biosciences). This system measures latent enzyme (pro-form and active forms but with a relatively low affinity with that bound to TIMPs, as reported by the manufacturer) after activation using p-aminophenylmercuric acetate. The exclusion of p-aminophenylmercuric acetate results in a measurement of the endogenous free active MMP-9 fraction. Total pro–MMP-9 and TIMP-1 levels were assessed in EDTA plasma samples using ELISA (product RPN 2614 and RPN 2611; Amersham Biosciences), the ratio of pro–MMP-9 (or latent) to active enzyme therefore indicating the degree of zymogen activation. The average coefficient of variance for both activity and ELISA assays was <5.5%.

Statistical Analysis
Statistical analysis was performed with StatView version 5.01 (SAS Institute). The distribution of continuous variables was assessed (kurtosis and skewness) and analyzed accordingly with either the Mann–Whitney U test or ANOVA with the Fisher protected least significant difference test.

Multiple logistic regression was used to test the interactive effects of other variables on the observed association between plasma active MMP-9 and ISR. A stepwise entry procedure was applied to identify significant or suggestive (P<0.15) confounders of either patient group or MMP level. The resulting winnowed model (WHR, BMI, plasma hs-CRP, high-density lipoprotein [HDL] cholesterol, TIMP-1, diabetes, extent of coronary disease, ACC/AHA lesion classification, total stent(s) length, number of sites stented, average stent diameter and medications) was not significantly different from an all-inclusive model.

Results are expressed as means±SD, except non-Gaussian variables, which are expressed as medians and interquartile range. Odds ratios are expressed with 95% CIs. A P value <0.05 was considered significant.


*    Results
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 *Results
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Demographic Confounders
Patients with ISR had no significant differences in gender, age, previous history of hyperlipidemia or hypertension, total cholesterol, low-density lipoprotein cholesterol, triglycerides, or tobacco smoking history compared with those without clinical evidence of restenosis (Table 1). In contrast, ISR patients had a significantly higher WHR, BMI, plasma hs-CRP, rate of triple vessel coronary disease, ACC/AHA lesion classification, and stent characteristics and lower plasma HDL cholesterol (Table 1). Patients with ISR were also significantly more medicated than symptom-free patients (Table 1).


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  		TABLE 1. Demographic Markers

Plasma Metalloproteinase and TIMP-1 Levels
Both latent MMP-3 and TIMP-1 were significantly higher in patients with triple vessel disease compared with subjects with single vessel disease (Figure ). When confounders were modeled, using logistic regression, the risk ratios for both markers became nonsignificant. Pro–MMP-9, latent, and active MMP-9 levels were not associated with the extent of coronary vessel disease (Figure). None of these plasma measures were associated with the index angiographic ACC/AHA lesion scores.


Figure 1
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  		Plasma MMP and TIMP-1 levels vs extent of coronary artery disease. Latent plasma MMP-3 was significantly increased in patients with triple vessel disease (Mann–Whitney U test *P<0.02) vs patients with either single or double vessel disease. TIMP-1 was significantly higher in triple (Mann–Whitney U test *P<0.01) vs single vessel disease. Error bars represent 95% CIs.

Active plasma MMP-9 and the ratio of active MMP-9 to pro–MMP-9 or latent MMP-9 were significantly higher in CAD patients with a history of ISR compared with the symptom-free stent group (Table 2), this finding being independent of other variables associated with the ISR group such as hs-CRP and extent of CAD (Figure).


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  		TABLE 2. Plasma MMP and TIMP-1 Levels in Symptom-Free CAD vs ISR Patients

The independence of plasma active MMP-9 as a risk indicator for ISR was confirmed using multiple logistic regression (Table 3). Active MMP-9 levels >2 ng/mL, observed in &60% of ISR patients but less than one third of symptom-free patients, resulted in an adjusted odds ratio of 6.5 (Table 3). Similarly, the ratio of active to pro–MMP-9 (or latent) MMP-9 appeared to be associated with ISR; however, this largely related to active MMP-9 levels because this association was abolished when the model also included active MMP-9.


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  		TABLE 3. Logistic Regression for Plasma Active MMP-9 Levels

The possible relationship between the MMP and TIMP-1 measures and the severity of ISR was examined by comparing plasma levels with Mehran classification, percentage restenosis, and the number of stented segments with ISR in each patient. The only significant association was in the subset of 31 ISR patients with multiple sites of ISR who had significantly higher levels of active MMP-9 compared with patients with either a single ISR lesion or no ISR (Table 4).


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  		TABLE 4. Active MMP-9 and TIMP-1 Levels vs No. of ISR Sites


*    Discussion
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 *Discussion
down arrowReferences
 
The pathology of ISR has been shown to consist primarily of neointimal smooth muscle proliferation among abundant, proteoglycan-rich, extracellular matrix.13–15 Such injury-induced intimal thickening has been shown to be associated with significantly enhanced MMP expression.16,17 Moreover, MMPs appear to play a key role in SMC migration after vascular injury, as indicated by various MMP inhibition studies reporting significant reductions in pathological remodeling.16,18,19

In this study, we observed significantly higher levels of the active form of MMP-9 in patients who had a previous history of ISR compared with patients who had undergone similar stent placement but had not developed symptoms of ISR in at least the first postinterventional year. Moreover, the level of active MMP-9 also appeared to be associated with the number of ISR lesions that had developed in each individual, this association appearing to be independent of known demographic and clinical risk factors. Although plasma TIMP-1, a key regulator of MMP tissue activity,20 was significantly increased in ISR patients, the association between active MMP-9 and ISR was independent of the levels of this inhibitory protein. The increased levels of active MMP-9 and the increased ratio of active to pro–MMP-9 (or latent MMP-9) isoforms support the conclusion that there is a significant shift in the zymogen activation equilibrium in patients prone to developing ISR. The lack of association between MMP levels and hs-CRP may indicate that this is, in part, attributable to a noninflammatory mechanism. A large number of bioactive molecules are known to a influence MMP activation,21 including other MMPs and plasmin. However, the exact mechanism for the increased MMP-9 activation observed in this study was beyond the scope of this current investigation.

The patients who developed ISR had all subsequently undergone further revascularization and were free of symptoms and cardiovascular events for ≥6 months. This is a critical inclusion criteria because we aimed, as much as possible, to exclude the effect of active symptomatic cardiac disease as a confounder in plasma biomarkers such as MMPs.22 Nevertheless, there were some clear differences between the ISR and non-ISR groups, including preinterventional coronary disease extent, stent length and diameter, ACC/AHA (index) lesion characteristics, adiposity measures, and circulating factors such as HDL cholesterol and C-reactive protein, which were adjusted for when comparing groups. Potential influences on circulating levels of MMPs, such as diurnal variation, ethnicity, age, and gender have been investigated in specifically designed studies.23 Although Asian and Middle Eastern ethnicity appears to be associated with MMP-9 levels, the majority of subjects in this study were white, and this is unlikely to be a confounding factor in this study. Statin24–27 and calcium channel antagonist28–31 treatment have been reported to influence MMP levels. Although we noted some slight but significant differences between use of these medications and MMP-9 levels (data not shown), we controlled for the influence of these variables in our regression analysis.

Multiple logistic regression clearly demonstrated that active plasma MMP-9 showed strong independent association with the ISR patient group. The ratio of active to total MMP-9 did not show independent association when the logistic regression model included active MMP-9, indicating that this parameter did not add any additional association beyond that of active MMP-9 alone. Active MMP-9 levels appeared most predictive at plasma concentrations >2 ng/mL, with similar odds ratios being observed in smaller numbers of patients at higher cut-off values. Although this study was limited by its retrospective nature, the observation of significantly stratified risk associated with elevated active MMP-9 levels in patients with multiple sites of ISR, after adjustment for possible confounders, suggests active MMP-9 levels warrant prospective testing as a useful prognostic marker for determining risk of ISR.

This study was undertaken in a patient population before the widespread availability of drug-eluting stents (DES) in the New Zealand public health system. Although it has not been shown conclusively that the excellent initial and midterm results of DES will persist in the long term,32,33 as opposed to delaying the onset of ISR, current evidence supports their efficacy.34 DES reduce both angiographically determined ISR rates from one third in patients with bare metals stents to <10%32 and the rate of major adverse cardiac events.32,35 Nevertheless, ISR restenosis is likely to persist as a significant clinical problem in the DES era, albeit at a lower rate than observed with bare metal stents. Whether plasma active MMP-9 is a useful marker of ISR in patients treated with DES needs to be determined in future studies.

In conclusion, this study indicates that the cleaved active form of MMP-9 is an independent indicator of risk of ISR in patients treated with bare metal stents. The prognostic value of this marker needs to be further evaluated in longitudinal studies and with regard to the new generation of DES, in which ISR remains a distinct, albeit less common, clinical entity.


*    Acknowledgments
 
We gratefully acknowledge the assistance of Dr Sally McCormick, Biochemistry Department, University of Otago, for measuring Lp(a) levels.

Sources of Funding

This work was supported by the Heart Foundation of New Zealand.

Disclosures

None.


*    Footnotes
 
Original received December 20, 2005; final version accepted April 26, 2006.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Ikeda U, Shimada K. Matrix metalloproteinases and coronary artery diseases. Clin Cardiol. 2003; 26: 55–59.[Medline] [Order article via Infotrieve]
  2. James TW, Wagner R, White LA, Zwolak RM, Brinckerhoff CE. Induction of collagenase and stromelysin gene expression by mechanical injury in a vascular smooth muscle-derived cell line. J Cell Physiol. 1993; 157: 426–437.[CrossRef][Medline] [Order article via Infotrieve]
  3. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res. 1994; 75: 539–545.[Abstract/Free Full Text]
  4. Mason DP, Kenagy RD, Hasenstab D, Bowen-Pope DF, Seifert RA, Coats S, Hawkins SM, Clowes AW. Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res. 1999; 85: 1179–1185.[Abstract/Free Full Text]
  5. Brown DL, Hibbs MS, Kearney M, Isner JM. Differential expression of 92-kDa gelatinase in primary atherosclerotic versus restenotic coronary lesions. Am J Cardiol. 1997; 79: 878–882.[CrossRef][Medline] [Order article via Infotrieve]
  6. George SJ, Zaltsman AB, Newby AC. Surgical preparative injury and neointima formation increase MMP-9 expression and MMP-2 activation in human saphenous vein. Cardiovasc Res. 1997; 33: 447–459.[Abstract/Free Full Text]
  7. Cedro K, Radomski A, Radomski MW, Ruzyllo W, Herbaczynska-Cedro K. Release of matrix metalloproteinase-9 during balloon angioplasty in patients with stable angina. A preliminary study. Int J Cardiol. 2003; 92: 177–180.[Medline] [Order article via Infotrieve]
  8. Hojo Y, Ikeda U, Katsuki T, Mizuno O, Fujikawa H, Shimada K. Matrix metalloproteinase expression in the coronary circulation induced by coronary angioplasty. Atherosclerosis. 2002; 161: 185–192.[Medline] [Order article via Infotrieve]
  9. Schoenhagen P, Vince DG, Ziada KM, Kapadia SR, Lauer MA, Crowe TD, Nissen SE, Tuzcu EM. Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by directional coronary atherectomy to intravascular ultrasound observations on coronary remodeling. Am J Cardiol. 2002; 89: 1354–1359.[CrossRef][Medline] [Order article via Infotrieve]
  10. Nikkari ST, Geary RL, Hatsukami T, Ferguson M, Forough R, Alpers CE, Clowes AW. Expression of collagen, interstitial collagenase, and tissue inhibitor of metalloproteinases-1 in restenosis after carotid endarterectomy. Am J Pathol. 1996; 148: 777–783.[Abstract]
  11. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation. 1990; 82: 1193–1202.[Abstract/Free Full Text]
  12. Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, Pichard AD, Kent KM, Stone GW, Leon MB. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999; 100: 1872–1878.[Abstract/Free Full Text]
  13. Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999; 99: 44–52.[Abstract/Free Full Text]
  14. Nakatani M, Takeyama Y, Shibata M, Yorozuya M, Suzuki H, Koba S, Katagiri T. Mechanisms of restenosis after coronary intervention: difference between plain old balloon angioplasty and stenting. Cardiovasc Pathol. 2003; 12: 40–48.[CrossRef][Medline] [Order article via Infotrieve]
  15. Skowasch D, Jabs A, Andrie R, Dinkelbach S, Schiele TM, Wernert N, Luderitz B, Bauriedel G. Pathogen burden, inflammation, proliferation and apoptosis in human in-stent restenosis. Tissue characteristics compared to primary atherosclerosis. J Vasc Res. 2004; 41: 525–534.[CrossRef][Medline] [Order article via Infotrieve]
  16. Li C, Cantor WJ, Nili N, Robinson R, Fenkell L, Tran YL, Whittingham HA, Tsui W, Cheema AN, Sparkes JD, Pritzker K, Levy DE, Strauss BH. Arterial repair after stenting and the effects of GM6001, a matrix metalloproteinase inhibitor. J Am Coll Cardiol. 2002; 39: 1852–1858.[Abstract/Free Full Text]
  17. Feldman LJ, Mazighi M, Scheuble A, Deux JF, De Benedetti E, Badier-Commander C, Brambilla E, Henin D, Steg PG, Jacob MP. Differential expression of matrix metalloproteinases after stent implantation and balloon angioplasty in the hypercholesterolemic rabbit. Circulation. 2001; 103: 3117–3122.[Abstract/Free Full Text]
  18. Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, Ivan E. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res. 2002; 91: 852–859.[Abstract/Free Full Text]
  19. Dollery CM, Humphries SE, McClelland A, Latchman DS, McEwan JR. Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury. Circulation. 1999; 99: 3199–3205.[Abstract/Free Full Text]
  20. Vu TH, Werb Z. Gelatinase B: structure, regulation and function. In: Parks W, Mecham R, eds. Matrix Metalloproteinases. San Diego, Calif: Academic Press; 1998.
  21. Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res. 2006; 69: 666–676.[Abstract/Free Full Text]
  22. Inokubo Y, Hanada H, Ishizaka H, Fukushi T, Kamada T, Okumura K. Plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are increased in the coronary circulation in patients with acute coronary syndrome. Am Heart J. 2001; 141: 211–217.[CrossRef][Medline] [Order article via Infotrieve]
  23. Tayebjee MH, Lip GY, Blann AD, Macfadyen RJ. Effects of age, gender, ethnicity, diurnal variation and exercise on circulating levels of matrix metalloproteinases (MMP)-2 and -9, and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2. Thromb Res. 2005; 115: 205–210.[CrossRef][Medline] [Order article via Infotrieve]
  24. Koh KK, Ahn JY, Jin DK, Han SH, Kim HS, Choi IS, Ahn TH, Shin EK, Jeong EM. Comparative effects of statin and fibrate on nitric oxide bioactivity and matrix metalloproteinase in hyperlipidemia. Int J Cardiol. 2004; 97: 239–244.[CrossRef][Medline] [Order article via Infotrieve]
  25. Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, Bernini F. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998; 18: 1671–1678.[Abstract/Free Full Text]
  26. Son JW, Koh KK, Ahn JY, Jin DK, Park GS, Kim DS, Shin EK. Effects of statin on plaque stability and thrombogenicity in hypercholesterolemic patients with coronary artery disease. Int J Cardiol. 2003; 88: 77–82.[CrossRef][Medline] [Order article via Infotrieve]
  27. Nagashima H, Aoka Y, Sakomura Y, Sakuta A, Aomi S, Ishizuka N, Hagiwara N, Kawana M, Kasanuki H. A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall. J Vasc Surg. 2002; 36: 158–163.[CrossRef][Medline] [Order article via Infotrieve]
  28. Boyle JR, Loftus IM, Goodall S, Crowther M, Bell PR, Thompson MM. Amlodipine potentiates metalloproteinase activity and accelerates elastin degradation in a model of aneurysmal disease. Eur J Vasc Endovasc Surg. 1998; 16: 408–414.[CrossRef][Medline] [Order article via Infotrieve]
  29. Canavesi M, Baldini N, Leonardi A, Sironi G, Bellosta S, Bernini F. In vitro inhibitory effect of lercanidipine on cholesterol accumulation and matrix metalloproteinases secretion by macrophages. J Cardiovasc Pharmacol. 2004; 44: 416–422.[Medline] [Order article via Infotrieve]
  30. Wada Y, Kato S, Okamoto K, Izumaru S, Aoyagi S, Morimatsu M. Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells. Int J Mol Med. 2001; 8: 561–566.[Medline] [Order article via Infotrieve]
  31. Zervoudaki A, Economou E, Pitsavos C, Vasiliadou K, Aggeli C, Tsioufis K, Toutouza M, Stefanadis C, Toutouzas P. The effect of Ca2+ channel antagonists on plasma concentrations of matrix metalloproteinase-2 and -9 in essential hypertension. Am J Hypertens. 2004; 17: 273–276.[Medline] [Order article via Infotrieve]
  32. Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet. 2004; 364: 583–591.[CrossRef][Medline] [Order article via Infotrieve]
  33. Bhatia V, Bhatia R, Dhindsa M. Drug-eluting stents: new era and new concerns. Postgrad Med J. 2004; 80: 13–18.[Abstract/Free Full Text]
  34. Fajadet J, Morice MC, Bode C, Barragan P, Serruys PW, Wijns W, Constantini CR, Guermonprez JL, Eltchaninoff H, Blanchard D, Bartorelli A, Laarman GJ, Perin M, Sousa JE, Schuler G, Molnar F, Guagliumi G, Colombo A, Ban Hayashi E, Wulfert E. Maintenance of long-term clinical benefit with sirolimus-eluting coronary stents: three-year results of the RAVEL trial. Circulation. 2005; 111: 1040–1044.[Abstract/Free Full Text]
  35. van Domburg RT, Lemos PA, Takkenberg JJ, Liu TK, van Herwerden LA, Arampatzis CA, Smits PC, Daemen J, Venema AC, Serruys PW, Bogers AJ. The impact of the introduction of drug-eluting stents on the clinical practice of surgical and percutaneous treatment of coronary artery disease. Eur Heart J. 2005; 26: 675–681.[Abstract/Free Full Text]



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