International Journal of Cardiology 190 (2015) 5662

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

The role of insulin resistance and metabolic risk factors on culprit

coronary plaque
Yae Min Park a, Seung Hwan Han a,, Jong Goo Seo a, Sihoon Lee b, Pyung Chun Oh a, Kwang Kon Koh a,
Kyounghoon Lee a, Soon Yong Suh a, Woong Chol Kang a, Taehoon Ahn a, In Suck Choi a, Eak Kyun Shin a
a
b

Division of Cardiovascular Disease, Gachon University Gil Hospital, Incheon, South Korea
Division of Endocrinology and Metabolism, Gachon University Gil Hospital, Incheon, South Korea

a r t i c l e

i n f o

Article history:
Received 2 February 2015
Received in revised form 15 April 2015
Accepted 18 April 2015
Available online 22 April 2015
Keywords:
Insulin resistance
Necrotic core
Virtual histology-intravascular ultrasound

a b s t r a c t
Background: Detailed relationships between insulin resistance (IR) and vulnerable plaque are not clear, therefore,
we sought the role of IR and metabolic risk factors on culprit coronary plaque.
Methods: Plaque components at a region of interest (ROI, 10 mm) were analyzed by virtual histology intravascular ultrasound. IR was dened as quantitative insulin sensitivity check index (QUICKI) 0.33. Seven metabolic
risk factors (5 risk factors for metabolic syndrome dened by ATP III, history of smoking, and hsCRP) for IR
were determined.
Results: The data for 150 (males 104) patients were analyzed. Patients with IR (n = 69) had greater necrotic core
(NC) at the ROI (21.2 15.8 mm3 vs 15.7 11.9 mm3, p = 0.02) than in patients without IR (n = 81). The NC at
the ROI was correlated with QUICKI (r = 0.16, p = 0.05), HbA1c (r = 0.24, p b 0.01), body mass index (r =
0.17, p = 0.04), presence of diabetes mellitus (r = 0.29, p b 0.001), hsCRP (r = 0.17, p = 0.04) and the numbers
of risk factors for IR (r = 0.41, p b 0.001). The multivariate analysis revealed that the numbers of risk factors for IR
was an independent factor for the NC at the ROI (beta coefcient = 0.44, p = 0.003), but QUICKI was not (beta
coefcient = 0.01, p = 0.94).
Conclusions: Instead of a single measurement of IR index or each metabolic risk factor, clustering of risk factors for
IR plays an important role on plaque vulnerability.
Condensed abstract: We investigated the role of insulin resistance (IR) on culprit coronary plaque. Patients with IR
had a greater amount of necrotic core in culprit coronary lesions than in patients without IR. Rather than a single
measurement of IR index or each metabolic risk factor, clustering of metabolic risk factors for IR plays an important role in plaque vulnerability in patients with coronary artery disease. Our study demonstrates the role of IR on
culprit coronary plaque and highlights the importance of the clustering of metabolic risk factors for IR in vulnerable plaque pathogenesis.
2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Vulnerable plaques are high-risk atherosclerotic lesions and complications of these plaques such as plaque rupture, luminal and mural
thrombosis, intraplaque hemorrhage, rapid progression in stenosis
severity and spasm lead to acute coronary syndrome [1]. Recently, spectral analysis of virtual histology intravascular ultrasound (VH-IVUS)

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CSA, cross sectional
area; DC, dense calcium; EEM, external elastic membrane; FBS, fasting blood sugar; FF, brofatty; HbA1c, glycated hemoglobin; hsCRP, high sensitivity C-reactive protein; IFG, impaired
fasting glucose; IR, insulin resistance; IVUS, intravascular ultrasound; MI, myocardial infarction; NC, necrotic core; QUICKI, using quantitative insulin sensitivity check index; ROI, region of interest; TCFA, thin cap broatheroma; VH-IVUS, virtual histology intravascular
ultrasound.
Corresponding author at: Gachon University Gil Medical Center, 1198 Kuwol-dong,
Namdong-gu, Incheon 405-760, South Korea.
E-mail address: shhan@gilhospital.com (S.H. Han).

http://dx.doi.org/10.1016/j.ijcard.2015.04.163
0167-5273/ 2015 Elsevier Ireland Ltd. All rights reserved.

radiofrequency data has demonstrated potential to provide detailed

quantitative information on plaque morphology and component:
brous, bro-fatty, dense calcium and lipid-rich necrotic core (NC) and
has been validated in studies of explanted human coronary segments
[2]. Unstable, lipid-rich plaques are believed to play a key role in these
events and to quantify the amount of NC in lesions could be a potential
measure for plaque vulnerability and further risk stratication [3].
Insulin resistance (IR) plays a major pathophysiological role in atherosclerotic cardiovascular diseases and is related to adverse cardiovascular outcome [410]. It has been reported that metabolic syndrome
was associated with the lipid-rich plaque in non-culprit coronary lesions and lesions in pre-intervention on three coronary vessels [11,12]
and hyperinsulinemia and abnormal glucose regulation were associated
with lipid rich coronary plaque by intracoronary imaging methods [10,
13]. However, there is no data for the independent role of IR index
and detailed relationships between IR including metabolic risk factors
and plaque vulnerability in culprit coronary lesions. In the present

Y.M. Park et al. / International Journal of Cardiology 190 (2015) 5662

study, we compared the plaque characteristics between patients with IR

and without IR and sought the role of IR including metabolic risk factors
on culprit coronary plaque.

57

calculated. Inter-observer correlations was excellent, with correlation

coefcients (r) being 0.90.
2.3. Coronary risk factors and lipids, metabolic parameters

2. Patients and methods

2.1. Patients and study design
This study was a cross sectional study which used the data from
the registry in patients with coronary artery disease (diameter
stenosis N 50%) who underwent VH-IVUS before percutaneous coronary intervention by operators' discretion. Between August 2008
and September 2011, 258 consecutive patients were enrolled. We
excluded patients with previous coronary stent insertion, manual
pullback of IVUS catheter, coronary artery bypass graft failure, and
patients with inadequate IVUS images. Also patients with a left ventricular ejection fraction of less than 35% and severe hepatic and
renal disease were excluded. To avoid the effects of insulin on insulin sensitivity index, diabetic patients who required insulin treatment were also excluded. In patients who underwent multi-vessel
VH-IVUS, the lesion with the worst diameter stenosis and more
complex morphology was selected for VH-IVUS analysis. Finally,
150 patients with analyzable IVUS images of native coronary vessels, pullback length greater than 10 mm, and with complete clinical
and laboratory value, were enrolled to this analysis. Hospital records
of patients were reviewed to obtain information on clinical demographics. The local Institutional Review Board approved this study,
and written informed consents were obtained from all patients.

Diabetes mellitus was dened as fasting glucose 126 mg/dL or 2 h

postprandial glucose 200 mg/dl or glycated hemoglobin (HbA1c)
6.5%, or if they were already being treated for this condition. Hypertension was dened as systolic blood pressure 140 mm Hg or diastolic
blood pressure 90 mm Hg, or if they were already being treated for
this condition. Body mass index (BMI) was calculated as body weight
in kilograms divided by the square of height in meters (kg/m2).
Blood samples for laboratory assays were obtained at the time
of coronary angiography following overnight fasting for at least 8 h.
Total cholesterol and triglycerides were analyzed with enzymatic
methods (Shinyang Chemical, Seoul, Korea), and high density lipoprotein (HDL) cholesterol by a direct immunoinhibition method (Wako
Pure Chemical, Osaka, Japan). LDL cholesterol was calculated using the
Friedewald equation [15]. Fasting blood sugar (FBS) was determined
by the hexokinase method (Shinyang Chemical, Seoul, Korea) using a
Hitachi 7600-110. Assays for plasma insulin levels were performed by
immunoradiometric assay (INSULIN-RIABEAD II, TFB, Inc., Tokyo,
Japan). Assays for glycated hemoglobin (HgA1c) were measured by
high performance liquid chromatography assay (VARIANT II TUR BO,
BIORAD, Inc., Hercules, California). High sensitivity C-reactive protein
(hsCRP) levels were determined with a turbidimetric assay (Denka
Seiken, Tokyo, Japan) using the Hitachi 7600-110. History of smoking
was obtained from all patients.
2.4. Insulin resistance (IR) index, numbers of risk factors for IR

2.2. IVUS procedure and analysis

Before the performance of gray-scale and VH-IVUS examination, patients were administered an intracoronary 0.2 mg of nitroglycerin to
prevent coronary spasm. A 20-MHz, 2.9 F IVUS imaging catheter
(Eagle Eye, Volcano Corp., Rancho Cordova, CA, USA) was advanced
more than 10 mm beyond the lesion; and automated pull-back was performed to a point more than 10 mm proximal to the lesion at a speed of
0.5 mm/s.
Quantitative volumetric gray-scale and VH-IVUS analyses were performed across the entire lesion segment, and cross-sectional analysis
was performed at the region of interest (ROI) and at the minimal
lumen site. The IVUS region of interest (ROI) was the most diseased
10 mm segment, identied by summarizing plaque volume in contiguous cross sections over an axial distance of 10 mm. Therefore, the segment with the greatest plaque volume constituted the most diseased
10 mm.
Conventional quantitative volumetric gray-scale IVUS analysis was
performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement
and Reporting of Intravascular Ultrasound Studies [14]. External elastic
membrane (EEM) and lumen cross-sectional areas (CSAs) were identied using automatic edge detection and manually corrected when necessary. Plaque plus media CSA was calculated as EEM minus lumen CSA;
and plaque burden was calculated as plaque plus media divided by EEM
CSA.
The IVUS-VH data were stored on a CD-ROM for ofine analysis.
Subsequently, VH-IVUS analysis classied the color-coded tissue into
four major components: (brous [F, labeled green], bro-fatty [FF, labeled greenish-yellow], dense calcium [DC, labeled white] and necrotic
core [NC, labeled red]) [3]. VH-IVUS analysis was reported as absolute
plaque amounts and as percentages (relative amounts). Thin-cap
broatheroma (TCFA) was dened as focal, NC-rich (10% of the CSA)
plaques being in contact with the lumen in a plaque burden 40%
over three consecutive frames. Analyses were conducted by 2 independent investigators unaware of the clinical data and the mean value was

IR index was determined from plasma glucose and insulin concentrations, using quantitative insulin sensitivity check index (QUICKI)
and calculated by using the formula; 1 / (log insulin (U/ml) + log glucose (mg/dL)) [16]. Patients with IR was dened as QUICKI 0.33 by the
previous studies [17,18].
Numbers of risk factors for IR (07) were derived from the sum of
risk factors which were related with IR from the previous reports
[1924]. These include 1) high BMI N 25 (kg/m2), 2) impaired fasting
glucose (IFG, FBS 110 mg/dL) or diabetes mellitus, 3) hypertension,
4) hypertriglyceridemia (triglyceride 150 mg/dL), 5) low HDL cholesterol (male b 40 mg/dL, female b 50 mg/dL), 6) history of smoking, and
7) high hsCRP N 1.0 mg/L. The diagnosis for metabolic syndrome was
made by patients who had more than 3 risk factors among 15) risk factors for IR. Each criterion for metabolic syndrome was slightly modied
for this study.
2.5. Cardiovascular diagnosis
Acute coronary syndromes included unstable angina, non-ST elevation myocardial infarction (MI), or ST elevation MI according to
American College of Cardiology/American Heart Association guidelines [25]. The diagnosis of acute MI was based on elevation of at
least 1 positive biomarker (creatine kinase, creatine kinase-MB, or
troponin T), characteristic electrocardiogram changes, and a history
of prolonged acute chest pain. Unstable angina pectoris was dened
as either angina with a progressive crescendo pattern or angina that
occurred at rest. Stable angina pectoris was dened as no change in
the frequency, duration, or intensity of symptoms within 4 weeks
before the intervention.
2.6. Data analysis
Patients were divided into two groups according to the presence
of IR. Variables were analyzed to compare the characteristics of patients with or without IR. Continuous variables were expressed as

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Y.M. Park et al. / International Journal of Cardiology 190 (2015) 5662

mean SD or median (25 percentile75 percentile) and compared

by Student t test or MannWhitney U test to evaluate differences
between mean values. Categorical variables were expressed as percentages and frequencies and compared by chi-square test or Fisher
exact test as appropriate. Correlations between the levels of risk factors and the VH-IVUS derived amount of NC were tested using
Pearson's coefcient of correlation. To determine the independent
parameters for the amount of NC, multivariate linear regression
analysis was performed. Values of p b 0.05 were considered signicant. All tests were 2-sided.
3. Results
3.1. Study population and baseline characteristics (Table 1)
Data for a total 150 consecutive patients (104 males with a median
age of 61 11.5, range 30 to 85) were analyzed. The prevalence of IR
was 69 patients (46.0%) among the patients. The baseline clinical characteristics are summarized in Table 1. Forty two patients (28%) had previous history of diabetes mellitus and the proportion was signicantly
higher in patients from the group with IR than without IR (36.2% vs.
21.0%, p = 0.04). BMI was signicantly higher in patients with IR
(25.9 3.3 kg/m2 vs 23.9 2.5 kg/m2, p b 0.001). The proportion of
the patients with acute coronary syndrome was similar between two
groups. Patients with IR showed higher triglyceride and hsCRP without
statistical signicance. Otherwise, there were no signicant clinical and
laboratory differences between two groups except for glucose, insulin
level and IR index. The proportion of metabolic syndrome and the numbers of risk factors for IR were signicantly greater in patients with IR
than in patients without IR (63.8% vs 34.6%, p b 0.001, 3.6 1.3 vs
2.6 1.3, p b 0.001, respectively).
3.2. Quantitative parameters of gray-scale and VH-IVUS
Gray-scale IVUS ndings are summarized in Table 2. The representative cases of VH-IVUS ndings on culprit coronary lesion in patients
with IR and without IR are illustrated in Fig. 1A and B. The volume of
total plaque plus media at the ROI was signicantly greater in patients
with IR than in patients without IR (113.4 51.4 mm3 vs 96.0
35.3 mm3, p = 0.03) although plaque burden (%) did not differ signicantly between two groups (Table 2).
At the ROI, the volume of brous tissue (48.2 24.8 mm3 vs. 38.7
19.7 mm3, p = 0.01) and NC (21.2 15.8 mm3 vs. 15.7 11.9 mm3,
p = 0.02) was signicantly greater in patients with IR than in patients
without IR. But the volume of FF and DC were comparable between
the two groups (Fig. 2).
3.3. Correlation between metabolic, lipid parameters and the amount of necrotic core
The amount of NC at the ROI had borderline correlation with the
level of QUICKI (r = 0.16, p = 0.05, Fig. 3A), and signicant correlation with HbA1c (r = 0.24, p b 0.01), BMI (r = 0.17, p = 0.04), presence
of diabetes mellitus (r = 0.29, p b 0.001), hsCRP (r = 0.17, p = 0.04)
and the numbers of risk factors for IR (r = 0.41, p b 0.001, Fig. 3B). All
lipid proles were not correlated with the volume of NC at the ROI
(0.06 r 0.05, 0.15 p 0.84).
In patients with IR, the amount of NC at the ROI was signicantly
correlated with the level of HbA1c (r = 0.27, p = 0.03), but not correlated with other metabolic and lipid parameters ( 0.05 r 0.13,
0.30 p 0.95).
In patients without IR, the amount of NC at the ROI was signicantly
correlated with the levels of BMI (r = 0.22, p b 0.05), but not correlated
with other metabolic and lipid parameters ( 0.12 r 0.34,
0.07 p 0.86).

Table 1
Baseline clinical characteristics.
IR

QUICKI
Age (years)
Male, n (%)
Clinical history, n (%)
Diabetes mellitus
Hypertension
Current or ex-smoker
Height (cm)
Weight (kg)
BMI (kg/m2)
Cardiovascular diagnosis, n (%)
Acute coronary syndrome
ST segment elevation MI
Non-ST segment elevation MI
Unstable angina pectoris
Stable angina pectoris
Ejection fraction (%)
Pro BNP (pg/mL)
Fasting blood sugar (mg/dL)
Insulin (mU/L)
Lipid levels (mg/dL)
Total cholesterol
Triglyceride
HDL cholesterol
Non-HDL cholesterol
LDL cholesterol
Hs CRP (mg/L)
Hemoglobin (g/dL)
White blood cells (103/mm3)
Platelet count (103/mm3)
Creatinine (mg/dL)
Metabolic syndrome (%)
Numbers of risk factors for IR
(number)
Culprit vessel
Left main
Left anterior descending
Left circumex
Obtuse marginal
Right

p
Value

Yes (n = 69)

No (n = 81)

0.298 0.023
58.7 12.2
48 (69.6%)

0.362 0.028
61.1 10.8
56 (69.1%)

0.00
0.19
0.96

25 (36.2)
43 (62.3)
30 (43.4)
163.4 9.3
69.2 10.8
25.9 3.3

17 (21.0)
41 (50.6)
27 (33.3)
163.8 8.3
64.3 9.6
23.9 2.5

0.04
0.15
0.20
0.80
0.004
0.00
0.35

38 (55.1)
9 (13.0)
14 (20.3)
15 (21.7)
31 (44.9)
60.0 12.6
122 (47318)
137.7 60.0
22.7 17.4

35 (43.2)
7 (8.6)
11 (13.6)
17 (21.0)
46 (56.8)
61.1 11.3
124 (49300)
100.3 24.2
6.7 2.5

173.0 33.6
162.0
(91.8227.0)
43.0 10.7
129.8 34.0
94.3 31.9
2.0 (0.710.7)
13.7 1.9
8.04 2.65
248.0 59.8
1.31 2.10
63.8
3.6 1.3

172.4 38.6
130.0
(96.0205.0)
44.0 11.1
128.4 37.1
96.8 38.8
1.6 (0.67.4)
13.6 1.8
7.33 2.56
248.4 65.8
0.94 0.45
34.6
2.6 1.3

1 (1.5)
35 (50.7)
11 (15.9)
2 (2.9)
20 (29.0)

2 (2.5)
46 (56.8)
16 (19.8)
1 (1.2)
16 (19.8)

0.56
0.66
0.00
0.00
0.92
0.21
0.55
0.81
0.67
0.39
0.67
0.10
0.97
0.16
0.00
0.00
0.63

Data are means SD or number (%) or median (25 percentile75 percentile).

IR = insulin resistance; QUICKI = quantitative insulin sensitivity check index; BMI =
body mass index; MI = myocardial infarction; BNP = brain natriuretic peptide; HDL =
high- -density lipoprotein; LDL = low- -density lipoprotein; HsCRP = high sensitivity C
reactive protein.
p b 0.00.

3.4. Independent predictors for the amount of NC at the ROI

The multivariate linear regression analysis (including all possible
parameters and the number of risk factors for IR) showed that number
of risk factors for IR was an independent factor for the amount of NC at
the ROI (beta coefcient = 0.44, p = 0.003). In other models (including
all possible parameters and the presence of metabolic syndrome), the

Table 2
Data for conventional intravascular ultrasound.
IR

ROI
EEM volume (mm3)
Lumen volume (mm3)
P & M volume (mm3)
Plaque volume (%)

p Value

Yes (n = 69)

No (n = 81)

167.8 60.8
54.4 17.8
113.4 51.4
65.6 9.7

153.1 45.2
57.1 22.4
96.0 35.3
62.3 10.7

0.13
0.46
0.03
0.08

Data are means SD.

IR = insulin resistance; ROI = region of interest; EEM = external elastic membrane; CSA =
cross sectional area; P & M = plaque plus media.

Y.M. Park et al. / International Journal of Cardiology 190 (2015) 5662

59

Fig. 1. The representative cases of VH IVUS ndings on culprit coronary lesion in patients with IR and without IR. (A) In a patient with IR, coronary angiography revealed signicant stenosis
at the mid LAD artery. VH-IVUS showed that the amount of NC at the ROI was 27.3 mm3 and NC at MLD was 4.5 mm2. (B) In a patient without IR, coronary angiography showed signicant
stenosis at the mid LAD. VH-IVUS revealed that the amount of NC at the ROI was 5.2 mm3 and NC at MLD was 0.7 mm2. VH-IVUS = virtual histology intravascular ultrasound; IR = insulin
resistance; LAD = left anterior descending; NC = necrotic core; ROI = region of interest; MLD = minimal luminal diameter.

presence of metabolic syndrome and history of smoking were independent predictors for the amount of NC at the ROI (beta coefcient = 0.35,
0.33, p = 0.02, 0.02, respectively). However, QUICKI was not an independent predictor for the amount of NC at the ROI in two models
(beta coefcient = 0.03, 0.21, p = 0.83, 0.16, respectively).

3.5. Correlation between the presence of metabolic risk factors and plaque
(Table 3)
Table 3 revealed the correlations between the presence of metabolic
risk factors and VH-IVUS derived plaque. Plaque plus media volume at
the ROI signicantly correlated with the presence of IR (r = 0.21,
p b 0.01), IFG or diabetes mellitus (r = 0.17, p b 0.01), metabolic syndrome (r = 0.22, p b 0.01) and the numbers of risk factors for IR (r =
0.22, p b 0.01). Plaque burden % signicantly correlated with the presence
of IFG or diabetes mellitus (r = 0.20, p b 0.05) and metabolic syndrome

(r = 0.22, p b 0.01) and the numbers of risk factors for IR (r = 0.22,

p b 0.01).
The amount of NC at the ROI was signicantly correlated with the
presence of IR (r = 0.20, p b 0.05), BMI (r = 0.18, p b 0.05), IFG or diabetes mellitus (r = 0.18, p b 0.05), hypertension (r = 0.22, p b 0.01),
history of smoking (r = 0.30, p b 0.001), and metabolic syndrome
(r = 0.32, p b 0.001) and the number of risk factors for IR (r = 0.41,
p b 0.001).
The correlation between the presence of metabolic syndrome and
the amount of NC at the ROI was also signicant in subgroup analysis according to the presence of IR (r = 0.30, p = 0.01 in patients with IR, r =
0.27, p = 0.02 in patients without IR). Similarly, the correlation between
the number of risk factors and the amount of NC at the ROI was also signicant in subgroup analysis whether the patients had IR (r = 0.31, p =
0.01) or not (r = 0.46, p b 0.001).
In addition, the amount of DC at the ROI was signicantly correlated
with the presence of IFG or diabetes mellitus (r = 0.20, p b 0.05),

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Y.M. Park et al. / International Journal of Cardiology 190 (2015) 5662

Table 3
Correlations between insulin resistance index, metabolic risk factors and plaque.
P plus M Plaque NC
DC
volume burden volume volume
(%)
Insulin resistance
High BMI
IFG or diabetes mellitus
Hypertension
Hypertriglyceridemia
Low HDL cholesterol
History of smoking
hsCRP N 1.0 mg/dL
Metabolic syndrome
Numbers of risk factors
for IR

hypertension (r = 0.25, p b 0.01), history of smoking (r = 0.17,

p b 0.05), metabolic syndrome (r = 0.25, p b 0.01) and the numbers
of risk factors for IR (r = 0.31, p b 0.001).

0.20
0.18
0.18
0.22
0.12
0.11
0.30
0.10
0.32
0.41

The presence of TCFA was not signicantly different whether the

patients had IR or not, however patients with metabolic syndrome
showed a signicantly higher incidence of TCFA than patients without
metabolic syndrome [(40/72) 55.6% vs. (28/78) 35.9%, p = 0.016]. By
the numbers of risk factors for IR, the presence of TCFA was signicantly
different (number 0 = 0%, number 1 = 10%, number 2 = 46.7%, number
3 = 51.4%, number 4 = 50%, number 5 = 68.4%, number 6 = 50%,
p b 0.001).
4. Discussion
The current study investigated the role of IR and metabolic risk
factors on coronary plaque vulnerability which was assessed by the
amount of NC in culprit coronary lesions using VH-IVUS. Patients with
IR showed a greater amount of NC at the ROI compared with patients
without IR. The amount of NC in culprit coronary plaque was signicantly correlated with the levels of HbA1c, C-reactive protein, BMI, the presence of metabolic syndrome and the numbers of risk factors for IR and
correlated with IR index with borderline signicance. Of interest, the
presence of metabolic syndrome and the numbers of risk factors for IR

60

40

20

0.21
0.11
0.15
0.06
0.04
0.05
0.11
0.08
0.18
0.21

r= 0.412
P<0.001

80

60

40

20

0.20

Volume of NC at ROI (mm3)

80

0.08
0.25
0.31

0.08
0.09
0.03
0.11
0.08
0.08
0.10
0.05
0.04
0.17

100

100

r= -0.160
p= 0.051

0.11
0.13
0.20
0.25
0.05
0.002
0.17

were independent predictors for the amount of NC in culprit coronary

plaque. Although previous studies have shown the relationships between IR and plaque vulnerability, our study is the rst to report that
clustering of risk factors for IR has a more important role for plaque vulnerability rather than each risk factor for IR including IR index.
Previous pathologic studies suggested that the decisive factor determining plaque vulnerability was plaque composition, rather than the
degree of luminal narrowing [26]. The culprit lesion in patients with
acute coronary syndrome was shown to be a relatively minor stenosis
(b50% of the percentage diameter stenosis) [27]. Furthermore, the NC
of atherosclerotic plaques was meaningful for ow restoration and
ST-segment elevation resolution after ST-segment elevation myocardial
infarction [28,29]. Early detection of vulnerable plaque before rupture is
an important clinical goal for the prevention of catastrophic events such
as acute coronary syndrome or sudden death and can be a guide for an
adjunctive pharmacological or device-based treatment plan [30]. In our
current study, we assessed plaque vulnerability by the amount of NC in
the culprit coronary lesion using VH-IVUS.
Regarding the associations of IR with increasing atherosclerotic
plaques and adverse cardiovascular outcome are not surprising because
IR has been well established as risk factors for cardiovascular disease.
However, few data are available for assessing the association with plaque
components and IR. Hyperinsulinemia and abnormal glucose regulation
was associated with lipid rich coronary plaque by intracoronary imaging
methods [10,13]. Similarly, patients with abnormal glucose regulation,

3.6. Thin cap broatheroma (TCFA)

Volume of NC at ROI (mm3)

0.16
0.07
0.20
0.12
0.02
0.04
0.02
0.08
0.22
0.22

F
volume

Data are Pearson's correlation coefcients.

P plus M = plaque plus media; NC = necrotic core; DC = dense calcium; FF = brofatty;
F = fatty; BMI = body mass index; IFG = impaired fasting glucose; HDL = high density
lipoprotein cholesterol; hsCRP = high sensitivity C reactive protein, IR = insulin
resistance.
p b 0.05.

p b 0.01.

p b 0.001.

Fig. 2. Comparisons of VH-IVUS parameters between patients with IR and without IR. The
patients with IR had a greater amount (volume) of brous tissue, and NC at the ROI than
in patients without IR. VH-IVUS = virtual histology intravascular ultrasound; IR = insulin
resistance; ROI = region of interest; F = brous; FF = bro-fatty; NC = necrotic core;
DC = dense calcium. p b 0.05.

0.21
0.09
0.17
0.10
0.04
0.03
0.16
0.06
0.22
0.22

FF
volume

0.25

0.30

0.35

QUICKI

0.40

0.45

0.50

The numbers of risk factors for IR

Fig. 3. Correlations of IR index (A) and the numbers of risk factors for IR (B) with the amount of NC at the ROI in all study subjects. IR = insulin resistance; NC = necrotic core; ROI = region
of interest; QUICKI = quantitative insulin sensitivity check index.

Y.M. Park et al. / International Journal of Cardiology 190 (2015) 5662

including impaired glucose regulation and diabetes mellitus, presented

more lipid rich plaque which may be related to the increased IR [10].
Taken together, there are still limited data for the detailed relationships
between metabolic risk factors and plaque components in patients with
coronary artery disease (CAD) and there are no data for the independent
role of IR index on culprit coronary artery plaque. Therefore, we compared
the plaque characteristics between patients with IR and without IR and
assessed the detailed relationships between metabolic risk factors and
the amount of VH-IVUS derived NC in culprit coronary artery plaque in
patients with CAD.
As we expected, patients with IR had a greater amount of NC than in
patients without IR. In addition, each risk factor for IR such as the levels
of HbA1c, hsCRP, and BMI was signicantly associated with the amount
of NC in culprit coronary plaque. However, the correlation between IR
index and the amount of NC showed borderline signicance. Interestingly, our study demonstrated that the clustering of risk factors for IR
in terms of the presence of metabolic syndrome and greater numbers
of risk factors for IR were independent risk factors for the amount of
NC in culprit coronary plaque. These results correspond with a recent
study using Integrated Backscatter-IVUS or VH-IVUS, on the impact of
metabolic syndrome identied by National Cholesterol Education Program in Adult Treatment Panel III criteria on tissue characteristics of
the coronary plaques which showed that patients with metabolic syndrome had a signicantly higher prevalence of lipid-rich plaque [11,
12]. In our current study, we also found that the correlation coefciency of the numbers of risk factors for IR with the amount of NC
was greater than in the presence of metabolic syndrome. Our results
suggest that the increased clustering of metabolic risk factors represent
a greater possibility of plaque vulnerability. These ndings are also supported by patients with metabolic syndrome showing a greater incidence of TCFA than in patients without metabolic syndrome in our
current study.
Taken together, our results demonstrated that the clustering of risk
factors for IR plays an important role on culprit coronary plaque vulnerability instead of a single measurement of IR index or each metabolic
parameter.
In addition, the amount of DC at the ROI signicantly correlated with
the presence of IFG or diabetes mellitus, hypertension, history of
smoking, metabolic syndrome and the numbers of risk factors for IR.
In these correlations, correlation co-efciency with DC at the ROI and
the numbers of risk factors for IR was much greater. These results are
consistent with previous ndings which showed the presence of high
calcication in patients with diabetes and metabolic syndrome [31,
32]. This result also suggests that patients with abnormal metabolic
risk factors may have a higher incidence of cardiovascular event rate
which was demonstrated by greater cardiovascular event rates in patients with a high calcication score by CT study [33].
Our study has some limitations. First, this was a retrospective analysis. Our analysis consisted of one vessel per patient, and a full segment of
one coronary tree was not evaluated. We dened ROI as the most diseased 10 mm segment which comprises only a small part of the entire
coronary arteries and thus selection of the ROI might include some
bias. Our results of plaque components were not conrmed by histology. Second, this single center study had a relatively small number of patients, thus possibly posing a risk of patient selection bias. A similar
relative amount of each plaque component at the ROI in patients with
IR and without IR can also be caused by a relatively small number of patients. Third, a single measurement of IR index may not represent the
long term status of IR. Lastly, there are some differences in patient characteristics between two groups according to the presence of IR. However, the intimate relationship is well known between insulin resistance
and metabolic syndrome including its risk factors. A large number of
prospective studies are warranted to conrm these data in the future.
In conclusion, patients with IR had a greater amount of NC in culprit
coronary lesions than in patients without IR. Rather than a single measurement of IR index or metabolic risk factors, clustering of risk factors

61

for IR plays an important role in plaque vulnerability in patients with

coronary artery disease.
Conicts of interest
The authors declared no conict of interest.
Acknowledgments
This was partly supported by the unrestricted grant from SanoAventis Korea (20115113). The authors of this manuscript have
certied that they comply with the Principles of Ethical Publishing in
the International Journal of Cardiology.
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