Impact of percutaneous coronary intervention on the levels of interleukin-6 and C-reactive protein in the coronary circulation of subjects with coronary artery disease

1. Impact of Percutaneous Coronary Intervention on the Levels
of Interleukin-6 and C-Reactive Protein in the Coronary
Circulation of Subjects With Coronary Artery Disease
Mahmoud M. Ramadan, MD*, Makoto Kodama, PhD, Wataru Mitsuma, MD, Masahiro Ito, PhD,
Takeshi Kashimura, MD, Taruna Ikrar, MD, Satoru Hirono, PhD,
Yuji Okura, PhD, and Yoshifusa Aizawa, PhD
Many clinical studies have evaluated the inflammatory response (mainly interleukin [IL]-6
and C-reactive protein [CRP]) after percutaneous coronary intervention (PCI) in patients
with coronary artery disease (CAD). The aim of this study was to verify the source of
possible elevation of IL-6 and CRP after PCI using coronary sinus sampling. We studied
87 subjects who underwent coronary angiography for diagnostic, therapeutic, or follow-up
purposes. Blood samples were taken by the PCI team during the catheterization study from
the coronary sinus. We measured coronary IL-6 levels by sandwich enzyme-linked immu-
nosorbent assay, and high-sensitivity CRP levels were measured by latex immunoneph-
elometry. The subjects were then classified according to their coronary angiographic
findings into non-CAD (no evidence of significant organic CAD), mild CAD (1 vessel
narrowed), and severe CAD (>2 vessels narrowed) groups. PCI (including stent deploy-
ment) was performed in 16 patients with CAD. The mean coronary IL-6 value was higher
in the severe than in the mild CAD group (3.67 2.48 vs 2.3 1.15 pg/ml, p 0.027). The
mean coronary IL-6 value was higher in the subjects who underwent PCI than in those who
did not (2.9 1.23 vs 1.87 0.9 pg/ml, p 0.037), and the same was found regarding CRP
(1.244 0.72 vs 0.498 0.51 mg/L, p 0.032). The coronary IL-6 values correlated
positively with the coronary CRP values (r 0.374, p 0.017). In conclusion, the increase
in coronary IL-6 and CRP levels after PCI in patients with CAD might be attributed to
their release from the coronary atheroma secondary to the direct mechanical effect applied
on the atheroma itself by balloon inflation and stent deployment. © 2006 Elsevier Inc. All
rights reserved. (Am J Cardiol 2006;98:915–917)
The present report was aimed at studying the impact of ogists. A significant lesion was defined as 75% stenosis of
percutaneous coronary intervention (PCI) on the levels of the arterial luminal diameter on coronary angiography by
interleukin (IL)-6 and C-reactive protein (CRP) in the cor- visual assessment according to the American College of
onary circulation of patients with coronary artery disease Cardiology/American Heart Association lesion classifica-
(CAD) and to verify the source of possible postprocedural tion scheme.1 The subjects were then classified according to
elevation of these markers using coronary sinus sampling. their coronary angiographic findings into non-CAD (no ev-
idence of significant organic CAD), mild CAD (1 vessel
Methods and Results narrowed), and severe CAD ( 2 vessels narrowed) groups.
The study group consisted of 87 subjects who were consec- PCI (including stent deployment) was performed in 16 pa-
utively admitted to the cardiology section of Niigata Uni- tients with CAD, and it was considered successful when a
versity Hospital from September 2004 to May 2005 because visually estimated reduction of stenosis to 50% residual
of suspected or already diagnosed CAD. The baseline clin- narrowing occurred after the procedure.
ical characteristics of the studied subjects are listed in Table Heparinized blood samples (5 ml each) were taken dur-
1. All subjects underwent coronary angiography for diag- ing the coronary angiographic session from the coronary
nostic, therapeutic, or follow-up purposes. Coronary lesions sinus by the PCI team immediately after completion of the
were characterized by 3 experienced interventional cardiol- coronary procedures. We recorded coronary sinus images at
the venous phase of left coronary angiography. A right
Division of Cardiology, First Department of Medicine, Niigata Uni-
Judkins catheter was inserted into the coronary sinus using
versity Graduate School of Medical and Dental Sciences, Niigata, Japan. a right jugular vein approach. Adequate posture was verified
Manuscript received February 16, 2006; revised manuscript received April by simultaneous fluoroscopy of the frontal and lateral
21, 2006 and accepted April 25, 2006. views. The obtained blood samples were then centrifuged at
Dr. Ramadan was supported by a research grant from the Japanese
Ministry of Education, Science and Culture, Tokyo, Japan.
3,000 rpm for 10 minutes at 4°C, and the sera were collected
*Corresponding author: Tel: 81-25-227-2185; fax: 81-25-227-0774. and immediately stored frozen at 80°C in small tubes for
E-mail address: amamod@med.niigata-u.ac.jp (M. Ramadan). future assay. In the coronary sinus sera, we measured the
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. www.AJConline.org
doi:10.1016/j.amjcard.2006.04.034

2. 916 The American Journal of Cardiology (www.AJConline.org)
Table 1
Baseline characteristics of the study population (n 87)
Variable Statistic
Age (yrs) 67.9 9.8
Men/women 60/27
Body mass index (kg/m2) 24 3.3
Smoker (current) 45 (52%)
Hypertension (essential) 56 (64%)
Diabetes mellitus 29 (33%)
CAD angiographic grade
Control (no significant organic coronary artery stenosis) 24 (28%)
Mild CAD (1 vessel narrowed) 33 (38%)
Severe CAD ( 2 vessels narrowed) 30 (34%)
Medications
Angiotensin-converting enzyme 45 (52%)
inhibitors/angiotensin-receptor blockers
-adrenergic receptor blockers 25 (29%)
Statins 38 (44%)
Values are presented as mean SD or number of subjects (percentages).
Figure 2. Mean coronary sinus CRP values in relation to existence and
severity of CAD.
cient. Differences were considered significant at a 2-sided
p 0.05.
The mean coronary IL-6 value was significantly higher in
the severe than in the mild CAD group (3.67 2.48 vs 2.3
1.15 pg/ml, respectively, p 0.027). The mean coronary IL-6
value was significantly higher in patients with CAD who un-
derwent PCI compared with those who did not (2.9 1.23 vs
1.87 0.9 pg/ml, respectively, p 0.037; Figure 1). Simi-
larly, the mean coronary CRP value was significantly higher in
patients with CAD who underwent PCI compared with those
who did not (1.244 0.72 vs 0.498 0.51 mg/L, respectively,
p 0.032; Figure 1). Although not statistically significant
(p 0.05, 1-way analysis of variance test), the coronary CRP
mean values showed a trend to increase as the existence and
severity of CAD increased (0.64 0.62, 0.87 0.72, and
0.94 0.66 mg/L for the non-CAD, mild CAD, and severe
Figure 1. Mean coronary sinus IL-6 and CRP values in relation to PCI use CAD groups, respectively; Figure 2). The coronary IL-6 values
in patients with CAD. ANOVA analysis of variance. correlated positively with the coronary CRP values (r 0.374,
p 0.017).
IL-6 levels with enzyme-linked immunosorbent assay kits
(Pelikine Compact, Sanqin Reagents, Amsterdam, The Discussion
Netherlands) using the “sandwich enzyme-linked immu- Many clinical studies have evaluated the inflammatory re-
nosorbent assay” principle. High-sensitivity CRP levels sponse (mainly IL-6 and CRP) after PCI in patients with
were measured using the latex immunonephelometry tech- CAD,2–7 and they have reported conflicting results about the
nique. source of elevation of these inflammatory markers, whether
Data analyses were performed using Statistical Package local (by way of their release from the coronary atheroma)
for Social Sciences for Windows, version 13 (SPSS, Inc., or systemic. However, in all these studies, peripheral blood
Chicago, Illinois). The normality of the distribution of the samples were assayed; thus, the data obtained could not
values of the different variables was checked using the precisely prove or rule out the coronary source of inflam-
1-sample Kolmogorov-Smirnov test. The results for contin- matory response after PCI. In our study, we tried to ap-
uous variables are expressed as mean SD. Differences in proach the coronary station as proximally as possible, so
the means of the continuous variables were assessed using that the assayed blood samples could represent—to a high
the 2-tailed Student’s t test. Correlation between continuous degree of confidence—the immediate IL-6 and CRP release
variables was assessed by the Pearson correlation coeffi- dynamics in the coronary milieu in response to PCI.

3. Coronary Artery Disease/Interleukin-6 and C-Reactive Protein 917
Our study showed that the mean coronary sinus IL-6 outcome with angioplasty for multivessel coronary disease: implications
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