© 2002 American Heart Association, Inc.
Letters to the Editor |
Periprocedural Kinetics in Serum Levels of Cytokines and Adhesion Molecules in Elective PTCA and Stent Implantation: Impact on Restenosis
University of Leipzig, Heart Center (P.C.S., E.K., G.S.), Department of Cardiology, Strümpellstrasse 39, 04289 Leipzig, Germany; Cardiovascular Division (P.C.S.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Zentralklinik Bad Berka (B.L.), Department of Cardiology, Bad Berka, Germany
To the Editor:
Coronary restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a significant clinical problem occurring in 
30% of patients even after wide accessibility and application of intraluminal stent implantation. Recent developments in stent design have made new techniques such as brachytherapy and drug-eluting stents available for clinical approaches; nonetheless, restenosis with its complex multifactorial genesis will continue to be an important problem with a major impact on long-term outcome of patients after coronary interventions. Several factors have been suggested to serve as predictors of the later occurrence of restenosis, but no serum parameter with predictive value has been clinically established so far.
The pathophysiology of coronary restenosis has not been fully elucidated; however, an initial vascular injury is supposed to initiate a local inflammatory response that induces the recruitment of circulating immune-competent cells through an increased expression and translocation of several adhesion molecules such as P-selectin, E-selectin, and monocyte chemoattractant molecule-1 (MCP-1).1,2 Migration of leukocytes, release of cytokines, and growth factors result in the induction of local inflammatory reactions and vascular remodeling.3 Patients with angina pectoris and acute myocardial infarction show a systemic inflammatory activation and elevated serum levels of vascular adhesion molecules.1,2 Therefore, the local vascular inflammation seems to be accompanied by alterations of serum parameters exhibiting a systemic inflammatory response toward local tissue damage.
We investigated periprocedural serum kinetics of cytokines (TNF
and IL-1ß) and adhesion molecules (ICAM-1, VCAM-1, E-selectin and P-selectin) from baseline to 48 hours after elective PTCA and intracoronary stent implantation in patients with stable angina pectoris (CCS II-III). Forty patients with stable angina pectoris and a left ventricular ejection fraction of >45% admitted for elective PTCA and stent implantation were prospectively included in this study. Before and 48 hours after intervention, venous blood samples were drawn from all individuals to assess kinetics in serum parameters over the periprocedural period. Control coronary angiography was performed after 6 months to assess the degree of in-stent restenosis. Angiograms were analyzed for degree of stenosis before and after stent implantation and at follow-up angiograms by using Quantitative Coronary Analysis (MEDIS). Restenosis was defined as >50% recurrent lumen diameter stenosis.
All patients received aspirin (100 mg daily) for the entire study period. For 4 weeks after stent implantation, all patients were administered an initial loading dose of 300 mg clopidrogrel followed by 75 mg of clopidrogrel daily. Furthermore, all patients received a standard medication of statins, ß-blockers, and an ACE-inhibitor.
Of the 40 patients initially included in this study, control angiography could be performed in 36 patients. Eleven (31%) patients showed evidence of restenosis (>50% diameter stenosis). Twenty-seven (75%) patients had one or more cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, smoking). Twenty-five (69%) patients were on antihypertensive treatment. Sixteen (44%) received lipid lowering medication. Diabetes mellitus was present in 9 (25%) patients. Fifteen (42%) patients were present or previous smokers (P was not significant for risk factors, baseline medication, and gender). One-vessel disease was present in 16 (47%) patients, two-vessel disease in 12 (33%) patients, and three-vessel disease in eight (22%) patients. Direct stent implantation was performed in 16 (44%) patients, whereas in the other 20 (56%) patients, the stent was implanted after predilatation with a conventional balloon. In 83% of the patients, a single stent was implanted. Four (13%) patients received two stents and one (4%) patient three stents.
All patients undergoing PTCA and stent placement showed a significant increase in serum TNF (baseline, 1.16±0.20 pg/mL; 48 hours, 1.47±0.26 pg/mL; P<0.05; Figure). Serum levels of IL-1ß did not change significantly in the whole study population. Patients with restenosis showed a slightly more pronounced but not significant increase in TNF (P=0.64). Serum levels of IL-1ß increased only in patients who developed restenosis (baseline, 0.17±0.13 pg/mL; 48 hours, 0.59±0.29 pg/mL; P<0.0001). In contrast, patients without restenosis showed a decrease in IL-1ß (baseline, 0.50±0.24 pg/mL; 48 hours, 0.27±0.27 pg/mL; P<0.05). The difference in changes of IL-1ß serum levels was statistically significant between the two subgroups (0.42±0.19 pg/mL vs -0.23±0.20 pg/mL; P<0.01) and showed a significant positive predictive value regarding the later occurrence of restenosis following PTCA and stent implantation (RR, 2.6; CI, 1.3 to 5.4).
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P<0.01 versus no restenosis). 
indicates no restenosis; 
, restenosis.The whole study population showed no significant differences in serum levels of ICAM-1, VCAM-1 and P-selectin 48 hours after stent implantation. Only E-selectin exhibited a significant decrease in all patients (2.47±0.22 vs 2.04±0.18 ng/mL; P<0.05). In patients without restenosis, serum levels of ICAM-1 (16.3±1.69 vs 14.7±1.42 ng/mL; P<0.0001) and VCAM-1 (7.86±0.58 vs 7.39±0.63 ng/mL; P<0.0001) showed a significant reduction. In patients with restenosis, ICAM-1 and VCAM-1 serum concentrations remained unchanged. Serum levels of E-selectin decreased in both groups of patients (2.35±0.46 vs 1.91±0.33 ng/mL; P<0.0001; 2.53±0.24 vs 2.1±0.21 ng/mL; P<0.0001). P-selectin decreased only in patients without restenosis (5.03±0.50 vs 4.11±0.50 ng/mL; P<0.001).
The present study demonstrates for the first time periprocedural kinetics in serum levels of cytokines and adhesion molecules within 48 hours after PTCA and intracoronary stent implantation. Our data confirm previous findings and support the hypothesis of a functional modulation of the progression of coronary artery disease by circulating molecules following vascular injury.
Inflammatory processes have been extensively investigated in coronary artery disease.4,5 Circulating immune cells as well as the vascular wall have been shown to contribute to increased systemic levels of cytokines in atherosclerosis and following vascular injury.6 Recently, the cytokine-generating capacities of monocytes (in particular IL-1ß) were found increased in patients with restenosis after PTCA.3 Moreover, in experimental carotid artery balloon angioplasty, the local expression of IL-1ß and its receptor increased after 6 hours and normalized within 24 hours. IL-1ß accumulates with neointimal smooth muscle cells, suggesting a distinct role in neointima formation.7 These studies are well in line with the findings of the present study demonstrating increased systemic levels of proinflammatory cytokines after PTCA and stent implantation in patients developing intracoronary restenosis. The crucial role of IL-1ß is further indicated by a pronounced decrease in patients who remain free of restenosis. Therefore, in addition to their role in the local response to vascular injury, proinflammatory cytokines are involved in the systemic inflammatory activation with predictive value in patients after PTCA and stent implantation. One might speculate the periprocedural time course of cytokines and adhesion molecules reflects the degree of vascular injury during the intervention and is also influenced by the specific practice of PTCA and stent implantation.
The decrease in soluble adhesion molecules only in patients without restenosis argues for an involvement of these molecules in the pathogenesis of coronary restenosis. Cellular adhesion molecules are expressed in developing neointima as well as endothelial cells and adhering platelets.2 After injury, intercellular adhesion molecules induce the recruitment and migration of mononuclear cells. Even though the origins of circulating adhesion molecules are not entirely clear, a main part seems to result from shedding or proteolytic cleavage from endothelial cells reflecting the expression of membrane-bound adhesion molecules. In patients developing restenosis after PTCA, levels of MCP-1 increased chronically with predictive value in regard to late lumen loss.1 Increased serum levels of soluble adhesion molecules have also been reported in patients with unstable angina and following intravascular intervention with an impact on morbidity and mortality.4,5
In conclusion, our findings suggest that patients at increased risk of restenosis following intracoronary intervention can be detected by a distinct time course of inflammatory serum parameters in the periprocedural period and, therefore, may profit from an early initiation of additional anti-inflammatory therapies. An advantage of our approach is the clinical practicability through a relatively easy routine measurement of serum parameters immediately before and 48 hours after intervention. The present study supports the hypothesis that inflammatory mechanisms in response to vascular injury are at least in part responsible for intracoronary restenosis and abnormalities can be detected in the peripheral blood stream.
References
1. Cipollone F, Marini M, Fazia M, Pini B, Iezzi A, Reale M, Paloscia L, Materazzo G, D’Annunzio E, Conti P, Chiarelli F, Cuccurullo F, Mezzetti A. Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol. 2001; 21: 237–334.
2. Hayashi S, Watanabe N, Nakazawa K, Suzuki J, Tsushima K, Tamatani T, Sakamoto S, Isobe M. Roles of p-selectin in inflammation, neointimal formation and vascular remodeling in balloon-injured rat carotid arteries. Circulation. 2000; 102: 1710–1717.
3. Tashiro H, Shimokawa H, Sadamatsu K, Aoki T, Yamamoto K. Role of cytokines in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty. Coron Artery Dis. 2001; 12: 107–113.[CrossRef][Medline] [Order article via Infotrieve]
4. Ridker PM, Hennekens CH, Roitman-Johnson B. Plasma concentration of soluble intercellular adhesion molecule-1and risks of future myocardial infarction in apparently healthy men. Lancet. 1998; 351: 88–92.[CrossRef][Medline] [Order article via Infotrieve]
5. Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J, AtheroGene Investigators. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001; 104: 1336–1342.
6. Hojo Y, Ikeda U, Katsuki T, Mizuno O, Fukazawa H, Shimada K. Chemokine expression in coronary circulation after coronary angioplasty as a prognostic factor for restenosis. Atherosclerosis. 2001; 156: 165–170.[CrossRef][Medline] [Order article via Infotrieve]
7. Wang X, Romanic AM, Yue TL, Feuerstein GZ, Ohlstein EH. Expression of interleukin-1beta, interleukin-1 receptor and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty. Biochem Biophys Res Commun. 2000; 271: 138–143.[CrossRef][Medline] [Order article via Infotrieve]
Institute for Arteriosclerosis Research, University of Muenster, Germany
In Response:
Shaskin et al show that SR-PSOX (CXCL16) mRNA is expressed in human T cells from peripheral blood using quantitative real-time RT-PCR. In accordance with our findings on SR-PSOX mRNA expression in smooth muscle and endothelial cells,1 their results indicate that expression of this scavenger receptor is not exclusively a feature of antigen-presenting cells. However, they report that SR-PSOX mRNA expression in T cells and human monocyte-derived macrophages (M
) is strongly downregulated following phorbol 12-myristate 13-acetate (PMA)/ionomycin induction, whereas Shimaoka et al found upregulation of SR-PSOX mRNA and protein in THP-1 cells after 3 d of stimulation with 160 nmol/L PMA.2 In agreement with the results of Shimaoka et al2 our experiments revealed a 1.7fold increase in SR-PSOX mRNA expression in THP-1 cells after 1 d incubation with 100 nmol/L PMA, and a 3.8fold increase after 3 d incubation using RT-PCR (unpublished data). It remains unclear whether the disparate results in these similar experiments are due to the use of PMA/ionomycin by Shaskin et al instead of PMA alone. Further experiments are in progress to elucidate the regulation of SR-PSOX in M and other cell types besides antigen-presenting cells.
References
1. Hofnagel O, Luechtenborg B, Plenz G, Robenek H. Expression of the novel scavenger receptor SR-PSOX in cultured aortic smooth muscle cells and umbilical endothelial cells. Arterioscler Thromb Vasc Biol. 2002; 22: 710–711.
2. Shimaoka T, Kume N, Minami M, Hayashida K, Kataoka H, Kita T, and Yonehara S. Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem. 2000; 275: 40663–40666.
Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, Japan
In Response:
By RT-PCR, we also have found that in the human T cell line, Jurkat cells express CXCL16/SR-PSOX mRNA, although their expression levels were much less than those found in THP-1 macrophages (Figure). This seems to be consistent with the observation shown in this letter by Shaskin et al that the CXCL16 mRNA expression level in T lymphocytes was approximately 10% of that in macrophages. Levels of CXCL16/SR-PSOX expression in U937 cells and MM6 cells might be less than those in macrophages. In addition, it remains unclear how much protein is expressed on the cell surface or how much of the protein is released as soluble molecules in T lymphocytes, because RT-PCR alone so far is the evidence for CXCL16/SR-PSOX expression in T cells. Therefore, pathophysiological roles of CXCL16/SR-PSOX in T cells remain totally speculative. Further studies by use of specific antibodies for CXCL16/SR-PSOX, as well as gene knockout mice, would tell us more concerning the roles of CXCL16/SR-PSOX in T cells.
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Footnotes
*These authors contributed equally to this work. 
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