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Is IL-10 a predictor of in-stent restenosis in stable and unstable angina patients undergoing coronary interventions?
International Journal of Cardiology 176 (2014) 1156–1157
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Is IL-10 a predictor of in-stent restenosis in stable and unstable angina patients undergoing coronary interventions? Georgia Karabela ⁎, George Karavolias, Antigoni Chaidaroglou, Christos Theleritis, Dimitrios Degiannis, Dimitrios Kremastinos, Stamatios Adamopoulos 2nd Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece
a r t i c l e
i n f o
Article history: Received 21 July 2014 Accepted 27 July 2014 Available online 3 August 2014 Keywords: Angina Angioplasty Plaque Inflammatory response Restenosis
Inflammation is an important feature of atherosclerotic lesions and associated with the pathogenesis of acute coronary syndromes (ACS) and the development of restenosis after coronary angioplasty (PCI) [1–3]. The aim of this study was: a) to investigate whether “active” coronary plaque disruption during PCI, activates further the inflammatory cascade in stable (SA) and unstable angina (UA) patients and b) to evaluate the possible association between this inflammatory activation, with restenosis. 43 patients with SA and 46 patients with UA underwent elective single-vessel PCI with stent implantation. Bare metal stents (BMS) were implanted in 70 patients and drug eluting stents (DES) in the rest 19 patients. Control groups consisted of 19 and 20 patients, with SA and UA respectively, who underwent coronary angiography. We assessed the levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), metalloproteinase-9 (MMP-9), tissue metalloproteinase inhibitor-2 (TIMP-2), monocyte chemoattractant protein-1 (MCP-1), T-cells chemoattractant protein IP-10, interleukine-6 (IL-6), C-reactive protein (CRP) and interleukine-10 (IL-10), in 43 SA and 46 UA patients, before 12 h and 40 h after PCΙ. Data are presented as mean ± SD for s-ICAM-1, s-VCAM-1, MCP-1, IP-10, MMP-9 and TIMP-2 or median (IQR) for IL-6, IL-10 and CRP variables. Repeated ANOVA was used to test for within-subject changes in scores on the afore-mentioned factors over time. Greenhouse–Geisser correction was used to adjust degrees of freedom for all F-tests if ⁎ Corresponding author at: 61, Nikitara Voula, Athens, Greece.
http://dx.doi.org/10.1016/j.ijcard.2014.07.258 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Mauchly's test of sphericity indicated heterogeneity of covariances. The un-paired t-test was used to compare the baseline levels between SA and UA. The chi-square test was used to examine the homogeneity of proportions between the 2 groups regarding the parameter of angina. The univariate logistic regression model has been applied in order to check whether there was any relation between the levels of the examined proteins (before, 12 h and 40 h post PCI) and the occurrence of restenosis. Multivariate logistic regression has also been applied in order to examine the joint possible effects of more than one potential risk factors (sex, smoking, family history, cholesterol, hypertension) to the occurrence of restenosis post PCI. Stepwise procedure has been used for the selection of the model that best fits our data. The nonparametric Mann–Whitney test was used to compare the IL-10 levels; 12 h post PCI, between the two groups of restenosis and no restenosis. All statistical tests were performed at significance level of p = 0.05. Statistical analysis has been carried out by using the SPSS package for Windows (version 11). In UA patients the baseline levels of IL-6 and CRP were significantly higher compared with SA (p b 0.05). During the procedure and until discharge, there were no acute major complications. In-stent restenosis was observed in 12 pts (14%). In SA, s-VCAM-1 increased significantly at 40 h (baseline vs. 12 h), (p = 0.01). Ιn UA, increased at 12 h (p = 0.006) and 40 h (p = 0.06) respectively. In SA, MMP-9 increased significantly at 12 h (p = 0.01) and 40 h (baseline vs. 40 h), (p = 0.002). Ιn UA, increased at 12 h (p = 0.01) and 40 h (p b 0.001) respectively. Both, in SA and UA, IL-6 increased significantly at 12 h (p = 0.04 and p = 0.01), and at 40 h (p = 0.01 and p b 0.001) respectively. In SA, CRP increased significantly at 12 h (p = 0.04) and 40 h (p = 0.01). Ιn UA, increased at 40 h (p = 0.001). The difference between the two last measures was also significant (12 h vs. 40 h), p b 0.004. Logistic regression analysis was primarily applied to the whole group of patients who BMS and DES {60(BMS) + 19(DES)} had been implanted. Univariate analysis showed a positive trend (p = 0.07), of IL-10, at 12 h post PCI, with the risk of restenosis. (RR = 1.11, CI = 0.991 to 1.2583, p-value = 0.07) (Table 1). Multivariate logistic regression did not identify any of the examined variables as having a significant correlation with restenosis. Thereafter, logistic regression analysis was applied to the BMS subgroup of patients (60 pts) in whom restenosis was observed.
G. Karabela et al. / International Journal of Cardiology 176 (2014) 1156–1157 Table 1 a) Correlations between cytokine levels and restenosis BMS and DES.
Table 2 b) Correlations between cytokine levels and restenosis BMS.
Univariate model
12 h post PCI
1157
Variables Variables
OR
SD Error
95% C.I. for OR
p-Value
IL-10 pg/ml
1.117
0.06808
0.991–1.2583
0.07
Univariate analysis showed that the elevation of IL-10, 12 h post PCI, is associated with increased risk of restenosis (RR = 1.14, CI = 1.006 to 1.293, p-value = 0.041). Multivariate logistic regression confirmed the strong association of the levels of IL-10 12 h post PCI with restenosis, (RR = 1.136, CI = 1.001 to 1.289, p = 0.049) (Table 2). Besides, the concentration of IL-10, 12 h post PCI, in the restenosis group (6 ± pg/ml) was significantly higher compared to the no restenosis group (3.28 ± pg/ml), (p = 0.0102). The Paired t-test for IL-10 levels for 12 h vs. 40 h showed that, the IL-10 levels in the restenosis group were significantly reduced from 12 to 40 h post-PCI (p = 0.027) compared to the no restenosis group. There was no significant correlation between the other inflammatory markers and in-stent restenosis. Although this study demonstrates that plaque disruption during angioplasty significantly activates a broad spectrum of inflammatory mediators, did not however manage to detect any significant correlation between s-ICAM-1, s-VCAM-1, MMP-9, IL-6, CRP, MCP-1, IΡ-10 and ΤΙΜΡ-2 with restenosis. On the contrary, the increase of IL-10 levels, 12 h post angioplasty, and the significantly decrease at 40 h, seems to correlate significantly with the occurrence of restenosis, in the BMS subgroup of patients. We might need a considerably larger population of patients, implanted with DES, to unmask such an important pathogenetic and prognostic correlation. By virtue of its main action concerning, the suppression of the activity of activated macrophages and also of T-lymphocytes, IL-10 represents an excellent example of a key mediator in the negative feedback of the immuno-inflammatory cascade [4]. Its presence therefore, not only verifies the intense immuno-inflammatory reaction to antigenic stimulation but also signifies an important mechanism through which the activated macrophages themselves produce and mobilize IL-10 in order to limit and terminate this reaction. We could presume that the presence of IL-10, 12 h post angioplasty, seems to correlate significantly with restenosis, due to: 1) the significant immune-inflammatory mobilization that has preceded and which
OR
SD Error
95% C.I. for OR
p-Value
Univariate model 12 h post PCI IL-10 pg/ml
1.140
0.07319
1.006–1.2933
0.041
Multivariate model 12 h post PCI IL10 pg/ml
1.136
0.07338
1.001–1.289
0.049
the presence of IL-10 proves, and 2) its favorable activity concerning the synthesis of collagen and extracellular matrix. If we therefore accept the presumption that restenosis is conducted in three stages: 1) immuno-inflammatory phase, 2) cell proliferation phase, and 3) synthesis of collagen-extracellular matrix and vessel remodeling [5], and we consider the presence of IL-10 necessary in the two of three of the above described phases, we could presume that probably the presence of IL-10 represents a prognostic index for the occurrence of restenosis post angioplasty. The limitations of this study concern the small number of patients. In conclusion, this study shows that the “active” rupture of the atheromatic plaque during angioplasty causes an additional immunoinflammatory reaction, in patients with stable and unstable angina. The present study suggested that from all this spectrum of inflammatory mobilization only the increase of IL-10 at 12 h and its significant decrease at 40 h after intervention seem to correlate significantly with the occurrence of restenosis, a factor which could be used as a prognostic index in the follow-up of patients post PCI. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–26. [2] Tracy RP. Inflammation in cardiovascular disease. Circulation 1998;97:2000–2. [3] Yarnell JWG, Baker IA, Sweetnam A, et al. Fibrinogen, viscosity, and white blood cell count are major risc factors for ischemic heart disease. Circulation 1991;88:836–44. [4] Moore KW, de W Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and inlterleukin10 receptor. Annu Rev Immunol 2001;19:683–765. [5] Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Is IL-10 a predictor of in-stent restenosis in stable and unstable angina patients undergoing coronary interventions? Georgia Karabela ⁎, George Karavolias, Antigoni Chaidaroglou, Christos Theleritis, Dimitrios Degiannis, Dimitrios Kremastinos, Stamatios Adamopoulos 2nd Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece
a r t i c l e
i n f o
Article history: Received 21 July 2014 Accepted 27 July 2014 Available online 3 August 2014 Keywords: Angina Angioplasty Plaque Inflammatory response Restenosis
Inflammation is an important feature of atherosclerotic lesions and associated with the pathogenesis of acute coronary syndromes (ACS) and the development of restenosis after coronary angioplasty (PCI) [1–3]. The aim of this study was: a) to investigate whether “active” coronary plaque disruption during PCI, activates further the inflammatory cascade in stable (SA) and unstable angina (UA) patients and b) to evaluate the possible association between this inflammatory activation, with restenosis. 43 patients with SA and 46 patients with UA underwent elective single-vessel PCI with stent implantation. Bare metal stents (BMS) were implanted in 70 patients and drug eluting stents (DES) in the rest 19 patients. Control groups consisted of 19 and 20 patients, with SA and UA respectively, who underwent coronary angiography. We assessed the levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), metalloproteinase-9 (MMP-9), tissue metalloproteinase inhibitor-2 (TIMP-2), monocyte chemoattractant protein-1 (MCP-1), T-cells chemoattractant protein IP-10, interleukine-6 (IL-6), C-reactive protein (CRP) and interleukine-10 (IL-10), in 43 SA and 46 UA patients, before 12 h and 40 h after PCΙ. Data are presented as mean ± SD for s-ICAM-1, s-VCAM-1, MCP-1, IP-10, MMP-9 and TIMP-2 or median (IQR) for IL-6, IL-10 and CRP variables. Repeated ANOVA was used to test for within-subject changes in scores on the afore-mentioned factors over time. Greenhouse–Geisser correction was used to adjust degrees of freedom for all F-tests if ⁎ Corresponding author at: 61, Nikitara Voula, Athens, Greece.
http://dx.doi.org/10.1016/j.ijcard.2014.07.258 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Mauchly's test of sphericity indicated heterogeneity of covariances. The un-paired t-test was used to compare the baseline levels between SA and UA. The chi-square test was used to examine the homogeneity of proportions between the 2 groups regarding the parameter of angina. The univariate logistic regression model has been applied in order to check whether there was any relation between the levels of the examined proteins (before, 12 h and 40 h post PCI) and the occurrence of restenosis. Multivariate logistic regression has also been applied in order to examine the joint possible effects of more than one potential risk factors (sex, smoking, family history, cholesterol, hypertension) to the occurrence of restenosis post PCI. Stepwise procedure has been used for the selection of the model that best fits our data. The nonparametric Mann–Whitney test was used to compare the IL-10 levels; 12 h post PCI, between the two groups of restenosis and no restenosis. All statistical tests were performed at significance level of p = 0.05. Statistical analysis has been carried out by using the SPSS package for Windows (version 11). In UA patients the baseline levels of IL-6 and CRP were significantly higher compared with SA (p b 0.05). During the procedure and until discharge, there were no acute major complications. In-stent restenosis was observed in 12 pts (14%). In SA, s-VCAM-1 increased significantly at 40 h (baseline vs. 12 h), (p = 0.01). Ιn UA, increased at 12 h (p = 0.006) and 40 h (p = 0.06) respectively. In SA, MMP-9 increased significantly at 12 h (p = 0.01) and 40 h (baseline vs. 40 h), (p = 0.002). Ιn UA, increased at 12 h (p = 0.01) and 40 h (p b 0.001) respectively. Both, in SA and UA, IL-6 increased significantly at 12 h (p = 0.04 and p = 0.01), and at 40 h (p = 0.01 and p b 0.001) respectively. In SA, CRP increased significantly at 12 h (p = 0.04) and 40 h (p = 0.01). Ιn UA, increased at 40 h (p = 0.001). The difference between the two last measures was also significant (12 h vs. 40 h), p b 0.004. Logistic regression analysis was primarily applied to the whole group of patients who BMS and DES {60(BMS) + 19(DES)} had been implanted. Univariate analysis showed a positive trend (p = 0.07), of IL-10, at 12 h post PCI, with the risk of restenosis. (RR = 1.11, CI = 0.991 to 1.2583, p-value = 0.07) (Table 1). Multivariate logistic regression did not identify any of the examined variables as having a significant correlation with restenosis. Thereafter, logistic regression analysis was applied to the BMS subgroup of patients (60 pts) in whom restenosis was observed.
G. Karabela et al. / International Journal of Cardiology 176 (2014) 1156–1157 Table 1 a) Correlations between cytokine levels and restenosis BMS and DES.
Table 2 b) Correlations between cytokine levels and restenosis BMS.
Univariate model
12 h post PCI
1157
Variables Variables
OR
SD Error
95% C.I. for OR
p-Value
IL-10 pg/ml
1.117
0.06808
0.991–1.2583
0.07
Univariate analysis showed that the elevation of IL-10, 12 h post PCI, is associated with increased risk of restenosis (RR = 1.14, CI = 1.006 to 1.293, p-value = 0.041). Multivariate logistic regression confirmed the strong association of the levels of IL-10 12 h post PCI with restenosis, (RR = 1.136, CI = 1.001 to 1.289, p = 0.049) (Table 2). Besides, the concentration of IL-10, 12 h post PCI, in the restenosis group (6 ± pg/ml) was significantly higher compared to the no restenosis group (3.28 ± pg/ml), (p = 0.0102). The Paired t-test for IL-10 levels for 12 h vs. 40 h showed that, the IL-10 levels in the restenosis group were significantly reduced from 12 to 40 h post-PCI (p = 0.027) compared to the no restenosis group. There was no significant correlation between the other inflammatory markers and in-stent restenosis. Although this study demonstrates that plaque disruption during angioplasty significantly activates a broad spectrum of inflammatory mediators, did not however manage to detect any significant correlation between s-ICAM-1, s-VCAM-1, MMP-9, IL-6, CRP, MCP-1, IΡ-10 and ΤΙΜΡ-2 with restenosis. On the contrary, the increase of IL-10 levels, 12 h post angioplasty, and the significantly decrease at 40 h, seems to correlate significantly with the occurrence of restenosis, in the BMS subgroup of patients. We might need a considerably larger population of patients, implanted with DES, to unmask such an important pathogenetic and prognostic correlation. By virtue of its main action concerning, the suppression of the activity of activated macrophages and also of T-lymphocytes, IL-10 represents an excellent example of a key mediator in the negative feedback of the immuno-inflammatory cascade [4]. Its presence therefore, not only verifies the intense immuno-inflammatory reaction to antigenic stimulation but also signifies an important mechanism through which the activated macrophages themselves produce and mobilize IL-10 in order to limit and terminate this reaction. We could presume that the presence of IL-10, 12 h post angioplasty, seems to correlate significantly with restenosis, due to: 1) the significant immune-inflammatory mobilization that has preceded and which
OR
SD Error
95% C.I. for OR
p-Value
Univariate model 12 h post PCI IL-10 pg/ml
1.140
0.07319
1.006–1.2933
0.041
Multivariate model 12 h post PCI IL10 pg/ml
1.136
0.07338
1.001–1.289
0.049
the presence of IL-10 proves, and 2) its favorable activity concerning the synthesis of collagen and extracellular matrix. If we therefore accept the presumption that restenosis is conducted in three stages: 1) immuno-inflammatory phase, 2) cell proliferation phase, and 3) synthesis of collagen-extracellular matrix and vessel remodeling [5], and we consider the presence of IL-10 necessary in the two of three of the above described phases, we could presume that probably the presence of IL-10 represents a prognostic index for the occurrence of restenosis post angioplasty. The limitations of this study concern the small number of patients. In conclusion, this study shows that the “active” rupture of the atheromatic plaque during angioplasty causes an additional immunoinflammatory reaction, in patients with stable and unstable angina. The present study suggested that from all this spectrum of inflammatory mobilization only the increase of IL-10 at 12 h and its significant decrease at 40 h after intervention seem to correlate significantly with the occurrence of restenosis, a factor which could be used as a prognostic index in the follow-up of patients post PCI. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–26. [2] Tracy RP. Inflammation in cardiovascular disease. Circulation 1998;97:2000–2. [3] Yarnell JWG, Baker IA, Sweetnam A, et al. Fibrinogen, viscosity, and white blood cell count are major risc factors for ischemic heart disease. Circulation 1991;88:836–44. [4] Moore KW, de W Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and inlterleukin10 receptor. Annu Rev Immunol 2001;19:683–765. [5] Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844.