202 Journal of Atherosclerosis and ThrombosisVol. 14, No.

4
Original Article
203 Small Dense LDL Cholesterol in MetS
Small Dense Low-density Lipoprotein Cholesterol is a Useful Marker
of Metabolic Syndrome in Patients with Coronary Artery Disease
Tsuyoshi Nozue
1
, Ichiro Michishita
1
, Yuki Ishibashi
1
, Shimpei Ito
1
, Taku Iwaki
1
, Ichiro Mizuguchi
1
,
Motohiro Miura
1
, Yasuki Ito
2
, and Tsutomu Hirano
3
1
Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Federation of National Public Service
Personnel Mutual Associations, Yokohama, Japan.
2
Research and Development Department, Denka Seiken Co., Ltd., Tokyo, Japan.
3
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Aim: An evaluation of the relation between small dense low-density lipoprotein cholesterol (sd-
LDL-C) levels measured by the heparin-magnesium precipitation method and metabolic syndrome
(MetS).
Methods: We have prospectively measured sd-LDL-C levels by the heparin-magnesium precipitation
method in 112 Japanese patients (male/female=80/32) with coronary artery disease (CAD) who re-
ceived percutaneous coronary intervention (PCI). Patients were diagnosed with MetS according to
modified Japanese criteria.
Results: A total of 36 patients (32%) met the criteria for MetS. Sd-LDL-C levels were significantly
higher in the MetS group than non-MetS group (20.71.5 mg/dL vs. 17.11.0 mg/dL, p=0.042),
especially among patients without lipid-lowering therapy (26.42.6 mg/dL vs. 17.51.5 mg/dL, p=
0.0034). Sd-LDL-C levels gradually increased with the number of components used to define MetS (0;
14.51.8 mg/dL, 1; 16.51.8 mg/dL, 2; 16.71.3 mg/dL, 3; 19.31.7 mg/dL, 4; 23.12.1 mg/dL,
5; 40.0 mg/dL, p=0.0071). High-sensitivity C-reactive protein (hs-CRP) levels were significantly high-
er in the patients with MetS (1.090.17 mg/L vs. 0.670.09 mg/L, p=0.0204).
Conclusion: The sd-LDL-C level measured by the heparin-magnesium precipitation method is a use-
ful marker of MetS in Japanese patients with CAD.
J Atheroscler Thromb, 2007; 14:202-207.
Key words; Small dense low-density lipoprotein cholesterol, Metabolic syndrome,
Coronary artery disease, High-sensitivity C-reactive protein
Introduction
Metabolic syndrome (MetS) is a clinical entity
characterized by visceral obesity, hypertension, hyper-
triglyceridemia, low high-density lipoprotein cholester-
ol (HDL-C), and glucose intolerance, although there
has been some incompatibility of diagnostic criteria
Address for correspondence: Tsuyoshi Nozue, Division of
Cardiology, Department of Internal Medicine, Yokohama
Sakae Kyosai Hospital, Federation of National Public Service
Personnel Mutual Associations, 132 Katsura-cho, Sakae-ku,
Yokohama 247-8581, Japan.
E-mail: nozue2493@yahoo.co.jp
Received: February 16, 2007
Accepted for publication: March 29, 2007
among countries. In Japan, a definition of and diagno-
stic criteria for MetS were established in April 2005
1)
.
The incidence of MetS was 7.8% in the general Japa-
nese population
2)
. The presence of MetS is associated
with increased coronary artery disease (CAD) events,
cardiovascular mortality, or reduced survival
3-5)
. MetS
is also reported to be predictive of subclinical athero-
sclerosis
6, 7)
.
Small dense low-density lipoprotein (sd-LDL) has
been demonstrated to be a new risk factor for the de-
velopment of CAD in Westerners
8, 9)
as well as in Jap-
anese, which have relatively low low-density lipopro-
tein cholesterol (LDL-C) levels
10)
. Subjects with MetS
typically do not have elevated levels of LDL-C. How-
ever, a qualitative abnormality in low-density lipopro-
202 Journal of Atherosclerosis and ThrombosisVol. 14, No. 4
Original Article
203 Small Dense LDL Cholesterol in MetS
tein (LDL) such as sd-LDL is recognized to be fre-
quently associated with MetS
8)
. LDL particle size is
usually measured by gradient gel electrophoresis using
non-denaturing polyacrylamide
11)
. This procedure re-
quires a long assay time and does not provide a quan-
titative determination of sd-LDL.
Recently, Hirano et al. established a simple and
rapid method for the measurement of small dense LDL
cholesterol (sd-LDL-C) concentrations using heparin-
magnesium precipitation
12, 13)
. This method is useful
for evaluating qualitative and quantitative abnormali-
ties in LDL, and may be applicable to a routine clini-
cal examination
13, 14)
.
In Japan as well as in other countries, the defini-
tion of and diagnostic criteria for MetS have not in-
cluded qualitative abnormalities in LDL. Therefore, in
this study, we evaluated the relation between sd-LDL-
C levels measured by the heparin-magnesium precipi-
tation method and MetS in Japanese patients with
CAD.
Subjects and Methods
Subjects
We have prospectively studied 112 patients (male/
female=80/32) with CAD who received percutaneous
coronary intervention (PCI) between November 2004
and June 2005. Patients were diagnosed with MetS ac-
cording to the Japanese criteria
1)
, that is, visceral obe-
sity (waist circumference 85 cm in men, 90 cm in
women) plus two or more of the following: (1) triglyc-
eride 150 mg/dL and/or HDL-C 40 mg/dL; (2)
systolic blood pressure 130 mmHg and/or diastolic
blood pressure 85 mmHg, or use of anti-hyperten-
sive medication; and (3) fasting plasma glucose 110
mg/dL, or history of diabetes. Since waist circumfer-
ence was not measured in this study, we used a body
mass index (BMI) of 25 kg/m
2
for visceral obesity.
Written informed consent was obtained from all pa-
tients.
Small Dense LDL Cholesterol Assay
The details and validation of this method have
been described elsewhere
12, 13)
. In brief, the precipita-
tion reagent (0.1 mL) containing 150 U/mL of hepa-
rin sodium salt and 90 mmol/L MgCl 2 was added to a
serum sample (0.1 mL), and incubated for 10 minutes
at 37. After centrifugation at 10,000 rpm (5,000g)
for 1 minute, sd-LDL and HDL were collected by fil-
tering off the more buoyant lipoproteins. Then the
penetrate solution containing sd-LDL and HDL was
removed for the measurement of LDL-C by a direct
and selective homogeneous assay method (LDL-EX,
Denka Seiken, Tokyo, Japan). This direct LDL-C as-
say was performed with an autoanalyzer (Type 7170;
Hitachi Ltd., Tokyo).
Laboratory Determination
Blood samples were obtained after an overnight
fast. Serum total cholesterol and triglyceride levels were
measured by standard enzymatic methods. Serum
LDL-C and HDL-C levels were measured by direct
homogeneous assay using detergents (LDL-EX, HDL-
EX, Denka Seiken).
Statistical Analysis
The statistical analyses were performed using Stat-
view 5.0 software (SAS Institute Inc., Cary, NC). All
values are expressed as the meanSEM. Differences
between the means were compared with the unpaired
t -test. The significance of any differences in propor-
tions was tested with a Chi-square analysis. A one-way
analysis of variance (ANOVA) and Fishers Protected
Least Significant Difference were used to compare
mean values of sd-LDL-C among groups from the
number of MetS components. A statistically signifi-
cant difference was defined as p0.05.
Results
A total of 36 patients (32%) met the criteria for
MetS defined in this study. The baseline characteris-
tics of the patients with or without MetS are listed in
Table 1. There were no significant differences in age,
sex, or total and LDL cholesterol levels between the
two groups. However, BMI, triglyceride levels, and the
frequency of diabetes mellitus were significantly high-
er and HDL-C levels were significantly lower in those
with MetS. The levels of fasting plasma glucose,
HbA1c, and the frequency of hypertension tended to
be higher in those with MetS. The rate of statin use
was similar between the two groups (Table 1). The cha-
racteristics of CAD with or without MetS are shown
in Table 2. There were no significant differences be-
tween the two groups.
Sd-LDL-C levels were significantly higher in those
with MetS (20.71.5 mg/dL vs. 17.11.0 mg/dL, p =
0.042) (Fig. 1a). In addition, apparent differences in
sd-LDL-C levels between the two groups were greater
when the patients who received lipid-lowering medica-
tions such as statins and fibrates were excluded (26.4
2.6 mg/dL vs. 17.51.5 mg/dL, p =0.0034) (Fig. 1b).
Sd-LDL-C levels gradually increased with the number
of components used to define MetS (0; 14.51.8 mg/
dL, 1; 16.51.8 mg/dL, 2; 16.71.3 mg/dL, 3; 19.3
1.7 mg/dL, 4; 23.12.1 mg/dL, 5; 40.0 mg/dL, p =
204 Nozue et al. 205 Small Dense LDL Cholesterol in MetS
0.0071) (Fig. 2).
High-sensitivity C-reactive protein (hs-CRP) lev-
els were significantly higher in the patients with MetS
(1.090.17 mg/L vs. 0.670.09 mg/L, p =0.0204)
(Fig. 3a). When we separated the patients according
to the type of CAD, we obtained the same results for
both stable angina (0.780.15 mg/L vs. 0.400.09
mg/L, p =0.0202) and acute coronary syndrome (ACS)
(1.640.35 mg/L, vs. 1.040.17 mg/L, p =0.0893)
(Fig. 3b).
Discussion
In the present study, sd-LDL-C levels measured
by the heparin-magnesium precipitation method were
significantly higher in the patients with MetS. Fur-
thermore, they increased significantly with the num-
ber of components used to define MetS. A previous
study based on gradient gel electrophoresis has dem-
onstrated that subjects with MetS have sd-LDL parti-
cles
15)
. In a recent sex-specific cross-sectional study, the
number of sd-LDL particles determined by nuclear
magnetic resonance spectroscopy was found to be gre-
Table 1. Baseline characteristics of patients with or without
metabolic syndrome
MetS ()
n =36 (32%)
MetS ()
n =76 (68%)
p Value
Age (years)
Sex (Male/Female)
Height (cm)
Body weight (kg)
BMI (kg/m
2
)
TC (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
TG (mg/dL)
DM (%)
FPG (mg/dL)
HbA1c (%)
Hypertension (%)
Statins (%)
Fibrates (%)
ACE inhibitors (%)
ARBs (%)
-blockers (%)
672
29/7
160.41.3
70.01.7
27.10.4
1837
1206
401
1399
28 (78%)
1196
6.90.3
29 (81%)
20 (56%)
4 (11%)
8 (22%)
15 (42%)
13 (36%)
701
51/25
159.81.0
58.81.1
22.90.3
1823
1133
471
1094
32 (42%)
1104
6.60.2
49 (64%)
41 (54%)
1 (1%)
19 (25%)
17 (22%)
14 (18%)
0.1410
0.1411
0.7036
0.0001
0.0001
0.8794
0.2309
0.0016
0.0005
0.0004
0.2088
0.5689
0.0839
0.8732
0.0191
0.7470
0.0347
0.0409
Data are expressed as the meanSEM or number (%). MetS, meta-
bolic syndrome; BMI, body mass index; TC, total cholesterol; LDL-C,
low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein
cholesterol; TG, triglyceride; DM, diabetes mellitus; FPG, fasting plas-
ma glucose; ACE, angiotensin-converting enzyme; ARB, angiotensin-
receptor blocker.
Table 2. Characteristics of coronary artery disease with or
without metabolic syndrome
MetS ()
n =36 (32%)
MetS ()
n =76 (68%)
p Value
Type of coronary artery
disease
ACS (%)
AMI (%)
UAP (%)
Stable angina (%)
Target vessel
LAD (%)
LCX (%)
RCA (%)
LMT (%)
Bypass (%)
Number of diseased
vessels
1 vessel
2 vessels
3 vessels
Type of stent
Bare metal stent (%)
Drug-eluting stent (%)
Stent diameter (mm)
Stent length (mm)
13 (36%)
11 (31%)
2 (6%)
23 (64%)
16 (44%)
9 (25%)
11 (31%)
0 (0%)
0 (0%)
9 (25%)
10 (28%)
17 (47%)
19 (53%)
17 (47%)
3.10.1
19.80.8
32 (42%)
22 (29%)
10 (13%)
44 (58%)
34 (45%)
11 (15%)
29 (38%)
1 (1%)
1 (1%)
30 (40%)
23 (30%)
23 (30%)
30 (39%)
46 (61%)
3.20.0
21.00.6
0.5443
0.5817
0.1748
0.1850
0.1341
0.2676
Data are expressed as the meanSEM or number (%). MetS, meta-
bolic syndrome; ACS, acute coronary syndrome; AMI, acute myocar-
dial infarction; UAP, unstable angina pectoris; LAD, left anterior de-
scending artery; LCX, left circumflex artery; RCA, right coronary
artery; LMT, left main trunk artery.
s
d
-
L
D
L
-
C

m
g
/
d
L

30
25
20
15
10
5
0
MetS MetS

NS

NS
a
s
d
-
L
D
L
-
C

m
g
/
d
L

30
25
20
15
10
5
0
MetS MetS

b
Fig. 1.
(a) Small dense LDL cholesterol (sd-LDL-C) levels with or with-
out metabolic syndrome (MetS). (b) Sd-LDL-C levels with or with-
out lipid-lowering therapy. All data are shown as the meanSEM.

p0.05,

p0.01. : Lipid-lowering therapy (), : Lipid-

lowering therapy ().
204 Nozue et al. 205 Small Dense LDL Cholesterol in MetS
ater in the patients with MetS and to increase with the
number of components for MetS
16)
.
How might MetS lead to an increase in sd-LDL?
There is substantial evidence that excess adiposity, es-
pecially accompanying diabetes or insulin resistance,
leads to increased free fatty acid production by adipo-
cytes
17)
. These free fatty acids are taken up by the liver
and used to produce triglyceride. As a consequence of
increased hepatic triglyceride synthesis, there is incre-
ased production and secretion of very low-density lipo-
protein (VLDL) particles by the liver
18)
. These VLDL
particles lead to an increased number of sd-LDL parti-
cles. Through the actions of cholesteryl ester transfer
protein (CETP), an appreciable amount of triglycer-
ide in VLDL may be exchanged for cholesterol ester
in plasma LDL
19)
. These triglyceride-enriched LDL
particles are a favored substrate for hepatic lipase and
may be transformed into smaller LDL by lipase-medi-
ated triglyceride hydrolysis
20)
.
Qualitative abnormalities of LDL are not includ-
ed in either the World Health Organization (WHO)
21)
,
the Adult Treatment Panel (ATP)
22)
, or the Japa-
nese criteria for MetS
1)
. Recently, a new definition of
MetS was developed by the International Diabetes
Federation (IDF)
23)
. The IDF Consensus has recom-
mended further research on a comprehensive list of
other components that should be considered as addi-
tions in future definitions of MetS. The list includes
adipose tissue biomarkers (adiponectin and leptin), apo-
lipoprotein B, LDL particle size, a formal measurement
of insulin resistance and an oral glucose tolerance test,
endothelial dysfunction, urinary albumin, inflamma-
tory markers (CRP, tumor necrosis factor alpha, and
interleukin-6), and thrombotic markers (plasminogen
activator inhibitor factor-1 and fibrinogen).
Hs-CRP level appears to be a strong predictor of
future cardiovascular events. The CRP provides pro-
gnostic information at all levels of LDL-C and the Fra-
mingham Risk Score
24)
. It is also clear that CRP levels
add clinically important prognostic information regar-
ding MetS
25)
. In this study, hs-CRP levels were signifi-
cantly higher in the patients with MetS.
The IDF Consensus recognizes that visceral obe-
sity is an important determinant of MetS, and that
there is a strong association between waist circumfer-
ence, cardiovascular disease, and other components of
MetS. The IDF also emphasizes that BMI is not suffi-
ciently sensitive to detect visceral obesity in different
ethnic groups. In this study, we tentatively defined
MetS using modified Japanese criteria. Since this study
was started before the Japanese criteria for MetS were
established, waist circumference was not measured.
Therefore, we used a BMI of 25 kg/m
2
according to
the criteria for obesity of the Japanese Society for the
h
s
-
C
R
P

m
g
/
L

3.0
2.5
2.0
1.5
1.0
0.5
0
MetS MetS



a
h
s
-
C
R
P

m
g
/
L

3.0
2.5
2.0
1.5
1.0
0.5
0
MetS MetS
NS
b
Fig. 3.
(a) High-sensitivity C-reactive protein (hs-CRP) levels with or with-
out metabolic syndrome (MetS). (b) Hs-CRP levels separated from
type of coronary artery disease. All data are shown as the mean
SEM.

p0.05,

p0.001. : Acute coronary syndrome, :

Stable angina.
45
40
35
30
25
20
15
10
5
0
0 1 4 3 2 5
s
d
-
L
D
L
-
C

m
g
/
d
L

Number of components for MetS
14.51.8
16.51.8
16.71.3
19.31.7
23.12.1
40





Fig. 2.
Distribution of small dense LDL cholesterol (sd-LDL-C) levels acc-
ording to the number of components for the definition of metabo-
lic syndrome (MetS). All data are shown as the meanSEM.

p
0.05,

p0.01. p=0.0071 with Fishers Protected Least Significant

Difference.
206 Nozue et al. 207 Small Dense LDL Cholesterol in MetS
Study of Obesity
26)
, as the cut-off point for visceral
obesity.
In the present study, sd-LDL-C levels measured
by the heparin-magnesium precipitation method in-
creased with the number of components used to de-
fine MetS. Furthermore, sd-LDL-C levels were signifi-
cantly lower with than without lipid-lowering therapy
in the patients with MetS. As several statins have been
known to decrease sd-LDL levels
27, 28)
, our data also ind-
icate the effect of statins on sd-LDL-C in those with
MetS.
Conclusion
In conclusion, the sd-LDL-C level measured by
the heparin-magnesium precipitation method is a use-
ful marker of MetS in patients with CAD.
Study Limitations
There are some limitations regarding the inter-
pretation of these results and drawing of conclusions.
First, this study included 112 patients with CAD. The
sample size allowed for only a limited analysis of the
relation between MetS and sd-LDL-C levels. Second,
about 60% of the patients had received lipid-lowering
therapy. Third, since the study was started before Jap-
anese criteria for MetS were established, waist circum-
ference was not measured. Therefore, we tentatively
defined MetS using modified Japanese criteria.
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