Relation of Lipid Content of Coronary Plaque to Level of

Serum Uric Acid

Yuichi Saito, MD*, Takashi Nakayama, MD, Kazumasa Sugimoto, MD, Yoshihide Fujimoto, MD,
and Yoshio Kobayashi, MD

Elevated serum uric acid (SUA) level is known to be a prognostic factor in patients with
acute coronary syndrome (ACS). However, the pathogenesis of the relation between SUA
level and coronary plaque characteristics has not been fully evaluated. The aim of this study
was to investigate the relation between SUA level and plaque composition of nonculprit
lesions in patients with ACS. A total of 81 patients with ACS who underwent intravascular
ultrasound (IVUS)eguided percutaneous coronary intervention were included. They were
classified into 3 groups according to tertiles of SUA level. Using integrated backscatter (IB)
eIVUS system, tissue components were classified into 4 categories: calcium deposits, dense
fibrosis, fibrosis, and lipid. Tertiles of SUA level were as follows: low tertile <5.0 mg/dl;
intermediate tertile 5.0 to 6.4 mg/dl; and high tertile >6.4 mg/dl. There was a trend toward
greater vessel volume in the high tertile group than in the low and intermediate tertile
groups (19.4 – 3.7 vs 17.4 – 4.4 vs 16.7 – 4.1 mm3/mm, p [ 0.05). There was no significant
difference in lumen volume between the 3 groups. Plaque volume was significantly greater
in the high than in the low tertile group (8.6 – 2.4 vs 6.7 – 2.2 mm3/mm, p [ 0.01).
IB-IVUS analysis demonstrated greater lipid (59.1 – 9.1% vs 49.7 – 10.9% vs 51.1 – 9.3%,
p [ 0.001) and less fibrous components (36.8 – 7.8% vs 44.3 – 7.8% vs 43.2 – 6.7%,
p <0.001) in the high than in the low and intermediate tertile groups. Multivariate analysis
showed high SUA as an independent predictor of increasing lipid volume. In conclusion,
elevated SUA level is associated with greater lipid content of coronary plaque in patients
with ACS than in patients with normal levels. Ó 2015 Elsevier Inc. All rights reserved.
(Am J Cardiol 2015;116:1346e1350)

Elevated serum uric acid (SUA) level is associated with
cardiovascular events in patients with coronary risk factors
such as hypertension or diabetes.1,2 It is also a prognostic
factor in patients with acute coronary syndrome (ACS),
especially ST-segment elevation myocardial infarction.3e5
However, the pathogenesis of the relation between SUA
level and coronary plaque characteristics has not been fully
evaluated. Integrated backscatter-intravascular ultrasound
(IB-IVUS) allows quantitative detection of coronary plaque
components in vivo.6e8 Increased lipid-rich plaque is an
independent predictor of cardiovascular events after percu-
taneous coronary intervention (PCI).9 It is also associated
with no-reflow and slow-flow phenomenon during PCI.10,11
The aim of this study was to investigate the relation between
SUA level and plaque composition of nonculprit lesions in
patients with ACS.
Methods
From April 2012 to December 2014, a total of 313 pa-
tients with ACS underwent PCI at Chiba University Hos-
pital. Patients were considered eligible for this study when
Department of Cardiovascular Medicine, Chiba University Graduate
School of Medicine, Chiba, Japan. Manuscript received June 23, 2015;
revised manuscript received and accepted July 30, 2015.
See page 1348 for disclosure information.
*Corresponding author: Tel/fax: (þ81) 43-226-2340.
E-mail address: policemaccho@yahoo.co.jp (Y. Saito).
SUA measurement on admission was available and IVUS-
guided PCI was performed. The major criteria for exclu-
sion were patients receiving antihyperuricemic agents before
admission, hemodialysis, no stent implantation, emergent
surgery or mechanical support (e.g., extracorporeal mem-
brane oxygenation), cardiopulmonary arrest, inhospital
adverse events, and a target lesion in stented segment. Pa-
tients who had no analyzable nonculprit plaque (plaque
burden >20% and at least 5-mm length) were also excluded.
Thus, 81 patients were included in the study (Figure 1).
They were classified into 3 groups according to tertiles of
SUA level.
ACS was defined as unstable angina or acute myocardial
infarction (MI) <48 hours from the onset. The diagnosis of
acute MI was based on the third universal definition of MI.12
Unstable angina was diagnosed using Braunwald criteria
plus documentation of significant coronary artery disease on
coronary angiography.13 The ethics committee of Chiba
University approved the study.
All grayscale IVUS and IB-IVUS were performed after
intracoronary administration of isosorbide dinitrate 1 to
2 mg. They were acquired with a commercially available
IVUS imaging system (VISIWAVE, Terumo, Tokyo,
Japan) using a 43-MHz mechanically rotating IVUS catheter
(View IT, Terumo) with a motorized transducer pullback
speed of 0.5 mm/s. All IVUS measurements were performed
by an experienced investigator, who was unaware of the
patients’ clinical characteristics, according to the American
College of Cardiology Clinical Expert Consensus Document

0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2015.07.059
 Coronary Artery Disease/Association Between Vulnerable Plaque and Uric Acid 1347

Table 1
Baseline characteristics
Variable Tertile p Value

Low Intermediate High

(n ¼ 27) (n ¼ 27) (n ¼ 27)

Men 17 (63%) 24 (89%) 25 (93%) 0.01

Age (years) 65.5  9.2 66.0  14.3 63.8  12.7 0.79
Body mass index 23.3  3.5 23.5  3.2 25.2  3.2 0.08
(kg/m2)
Hypertension 20 (74%) 16 (59%) 19 (70%) 0.49
Diabetes mellitus 11 (41%) 7 (26%) 9 (33%) 0.59
Dyslipidemia 17 (63%) 19 (70%) 20 (70%) 0.68
Current smoker 10 (37%) 11 (41%) 11 (41%) 0.95
Prior myocardial 2 (7%) 2 (7%) 3 (11%) 0.86
infarction
eGFR (ml/min/1.73m2) 85.1  20.9 72.0  17.6 60.3  18.5 <0.001
Serum uric acid (mg/dl) 4.0  1.0 5.5  0.4 7.6  1.1 <0.001
Culprit coronary artery
Right 7 (26%) 7 (26%) 10 (37%)
Left anterior 10 (37%) 12 (44%) 13 (48%)
descending
Left circumflex 10 (37%) 8 (30%) 4 (15%) 0.45
Clinical presentation
Figure 1. Study flow chart. CPA ¼ cardiopulmonary arrest. Unstable angina 3 (11%) 5 (19%) 4 (15%)
pectoris
on Standards for Acquisition, Measurement, and Reporting NSTEMI 8 (30%) 9 (33%) 14 (52%)
of Intravascular Ultrasound Studies.14 Offline analysis STEMI 16 (59%) 13 (48%) 9 (33%) 0.35
including IB-IVUS analysis was performed using a Medication on admission
Statin 8 (30%) 9 (33%) 9 (33%) 0.95
computerized system (VISIATLAS, Terumo, Tokyo,
ACE-I or ARB 7 (26%) 13 (48%) 11 (41%) 0.24
Japan). IVUS measurement was performed from the ostium Calcium channel 8 (30%) 7 (26%) 7 (26%) 0.94
of the culprit artery to the site 5-mm proximal to the prox- blocker
imal edge of the stent. For each 0.5 mm of axial length, Diuretic 1 (4%) 1 (4%) 5 (19%) 0.08
lumen and external elastic membrane cross-sectional areas
were manually measured. Volumetric IVUS data were pre- Hypertension was defined by systolic blood pressure 140 mm Hg,
sented as total volume per lesion length (mm3/mm) for diastolic blood pressure 90 mm Hg, or taking antihypertensive medica-
correcting the differences of lesion length.8,15 Tissue com- tions. Diabetes mellitus was defined by glycated hemoglobin 6.5%, or
taking diabetic medications. Dyslipidemia was defined by high-density
ponents were classified into 4 categories: calcium deposits
lipoprotein <40 mg/dl, low-density lipoprotein >140 mg/dl, fasting tri-
(red), dense fibrosis (yellow), fibrosis (green), and lipid glyceride >150 mg/dl, or taking lipid-lowering medications.
(blue) according to signal level.16 The percentage of lipid, ACE-I ¼ angiotensin converting enzyme inhibitor; ARB ¼ angiotensin
fibrosis, dense fibrosis, and calcium deposits plaque volume receptor blocker; eGFR ¼ estimated glomerular filtration rate; NSTEMI ¼
(each component volume/plaque volume  100) were noneST-segment elevation myocardial infarction; STEMI ¼ ST-segment
calculated. elevation myocardial infarction.
Statistical analysis was performed with SAS statistical
software package version 9.4 (SAS Institute, Cary, North
Carolina). Data are expressed as the mean  standard de-
viation or frequency (%). Continuous variables were Table 2
compared using analysis of variance. Categorical variables Intravascular ultrasound analysis
were compared with the chi-square statistics or Fisher’s Variable Tertile p Value
exact test. A value of p <0.05 was considered significant.
Low Intermediate High
Univariate analysis for variables in Table 1 was performed
(n ¼ 27) (n ¼ 27) (n ¼ 27)
using linear regression analysis of rank-transformed out-
comes. Including only variables with a p value of <0.2 on Lesion length (mm) 15.6  10.1 20.0  12.6 14.2  10.1 0.14
univariate analysis, multivariate analysis was performed Minimum lumen 8.2  2.9 6.1  2.6 7.6  3.8 0.05
using multiple linear regression analysis of rank- area (mm2)
transformed outcomes. Vessel area (mm2) 16.4  4.3 14.4  5.0 17.5  4.8 0.06
Plaque area (mm2) 8.3  3.6 8.3  3.9 9.8  3.4 0.22
Lumen volume 10.7  3.2 9.9  3.1 10.6  3.2 0.60
Results (mm3/mm)
Tertiles of SUA level were as follows: low tertile Vessel volume 17.4  4.4 16.7  4.1 19.4  3.7 0.05
(mm3/mm)
<5.0 mg/dl; intermediate tertile 5.0 to 6.4 mg/dl; and
Plaque volume 6.7  2.2 7.4  2.7 8.6  2.4 0.01
high tertile >6.4 mg/dl. Table 1 lists baseline character- (mm3/mm)
istics. Table 2 provides IVUS measurements. IB-IVUS
1348 The American Journal of Cardiology (www.ajconline.org)

Figure 2. Integrated backscatter intravascular ultrasound analysis.

analysis demonstrated greater lipid and less fibrous com-
ponents in the high tertile group than in the low and
intermediate tertile groups (Figure 2). Figure 3 shows the
representative IVUS images in patients with low and high
SUA levels. Multivariate analysis showed high SUA level
as an independent predictor of greater lipid plaque vol-
ume (Table 3).
Discussion
The present study showed that SUA level was a possible
surrogate marker of having vulnerable plaque in nonculprit
lesions of patients with ACS. To the best of our knowledge,
this is the first report describing association between
SUA level and coronary plaque characteristics by intravas-
cular imaging in patients with ACS. Although SUA has
antioxidant capacities,17 significant correlations have been
paradoxically reported between SUA level and surrogate
markers of atherosclerosis such as inflammation or
endothelial dysfunction.18e20 Uric acid may induce
positive remodeling as process of coronary atherosclerosis
through these underlying pathophysiological mechanisms.21
Oxygen-free radical is generated during purine metabolism
by activity of xanthine oxidase.22 It causes endothelial
dysfunction and impaired regulation of vascular tone.23
Recently, it has also been shown that xanthine oxidase
plays an important role in the transformation of macro-
phages into foam cells and the development of atheroscle-
rotic plaque.24
Previous studies have shown that elevated SUA level is
associated with cardiovascular events. In a series of 1,124
patients with acute MI, Kojima et al5 demonstrated higher
30-day major adverse cardiac events and long-term mor-
tality in patients with higher SUA level compared to those
with lower SUA level. Kaya et al showed higher rates of
inhospital and long-term major adverse cardiovascular
events in patients with ST-segment elevation MI with high
SUA level than in those with low SUA level.3 Cardiovas-
cular mortality, reinfarction, target vessel revascularization,
and severe heart failure were observed more frequently in
the high SUA group.
There is little information about relation between SUA
level and coronary plaque characteristics.25,26 Elevated SUA
level has been reported as a predictor of poor coronary
blood flow after primary PCI.27,28 No-reflow or slow-flow
phenomenon occurs in patients with greater lipid content
of coronary plaque.10,11 The present study showed greater
lipid and less fibrous components in the high tertile than in
the low and intermediate tertile groups. Using IB-IVUS,
Sano et al29 reported higher percentage of lipid area and
lower percentage of fibrous area in plaque of patients with
than without cardiovascular events during follow-up.
There are some limitations in the present study. First, the
number of patients was relatively small. Second, clinical in-
formation of long-term outcomes was not available, although
elevated SUA level was suggested as an indicator of greater
lipid content of coronary plaque. Third, we analyzed plaque
which was only proximal to the culprit lesion. It made the
studied segment shorter but the vessel size relatively uniform.
The vessel size correlated with lipid content of coronary
plaque.30 This is why we evaluated nonculprit plaque at the
segment proximal to the culprit lesion.
Disclosures
Dr. Kobayashi received research grant from Terumo
(Tokyo, Japan). The other authors have no conflicts of
interest to disclose.
 Coronary Artery Disease/Association Between Vulnerable Plaque and Uric Acid 1349

Figure 3. Representative images of grayscale and integrated backscatter intravascular ultrasound of nonculprit coronary plaques in patients with low (A) and
high (B) SUA levels. The percentages of lipid area and fibrosis area are 36.9% and 57.3% in the patient with a low SUA level and 69.6% and 29.6% in the
patient with a high SUA level, respectively. Blue ¼ lipid area, green ¼ fibrosis area, yellow ¼ dense fibrosis area, red ¼ calcium deposit area.

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