From the Center for Molecular and Vascular Biology (P.H., D.C.) and
Department of Cardiology (J.V., S.J., F.V.d.W.), University of Leuven,
Belgium.
Correspondence to P. Holvoet, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O&N, Herestraat 49, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be
Methods and Results—The study population contained 63 patients
with acute coronary syndromes (45 with acute myocardial
infarction and 18 with unstable angina pectoris), 35 nontransplanted
patients with angiographically confirmed stable angina, 28 heart
transplant patients with posttransplant CAD, 79 heart transplant
patients without CAD, and 65 control subjects. After correction for
age, sex, and LDL and HDL cholesterol, plasma levels of
oxidized LDL and MDA-modified LDL were significantly higher in patients
with CAD than in individuals without CAD
(r2=0.57 and
r2=0.26, respectively; both
P=0.0001). Plasma levels of MDA-modified LDL were
significantly higher in patients with acute coronary syndromes
than in individuals with stable CAD
(r2=0.65; P=0.0001) and were
associated with increased levels of troponin I and C-reactive protein
(r2=0.39 and
r2=0.34, respectively; both
P=0.0001). Plasma levels of oxidized LDL were not
associated with increased levels of troponin I and C-reactive protein
(r2=0.089 and
r2=0.063, respectively).
Conclusions—Elevated plasma levels of oxidized LDL are associated
with CAD. Elevated plasma levels of MDA-modified LDL suggest plaque
instability and may be useful for the identification of patients with
acute coronary syndromes.
An association between LDL oxidation and atherogenesis was first
suggested by experiments showing that oxidized LDL caused injury to
endothelial cells6 and was
further supported by studies showing a protective effect of
antioxidants against progression of
atherosclerosis.7 With the use of
a specific ELISA for oxidized LDL, an association between the extent of
coronary artery disease (CAD) in heart transplant patients and
plasma levels of oxidized LDL was recently established, suggesting that
oxidized LDL may be a marker of CAD.8 Previously,
elevated levels of MDA-modified LDL were detected in the plasma of
acute myocardial infarction (AMI) patients but not patients with stable
angina.9
We wanted to compare plasma levels of oxidized and MDA-modified LDL in
patients with acute coronary syndromes and patients with stable
CAD and to study the association between oxidized LDL and MDA-modified
LDL, respectively, and troponin I, a marker of ischemic
syndromes,10 11 and C-reactive protein, a marker
of inflammation.12
One hundred seven posttransplant patients (47 patients got a heart
transplant for dilated cardiomyopathy and 60
patients for end-stage CAD), who have been described in more detail
elsewhere,8 were reincluded. Twenty-eight of
these patients had angiographically determined posttransplant CAD.
Sixty five control subjects (31 men, 34 women; age, 52±1.3 years)
without a history of atherosclerotic cardiovascular
disease were studied (Table 1
Venous blood samples8 were taken in the fasting
state in control subjects, patients with stable angina, and
posttransplant patients. In patients with acute coronary
syndromes, blood samples were taken on admission before the start of
treatment.
Lipoproteins: Isolation and Modification
Assays
Immunodetection of Oxidized and MDA-Modified LDL in
Coronary Atherosclerotic Lesions
Statistical Analysis
Plasma levels of MDA-modified LDL were 0.37±0.017 mg/dL in control
subjects, similar in patients with stable angina pectoris and heart
transplant patients without and with posttransplant CAD, 2.6-fold
higher (P<0.001) in patients with unstable angina pectoris,
and 3.1-fold higher (P<0.001) in AMI patients (Figure 1
Plasma levels of troponin I were 0.025±0.0031 ng/mL in control
subjects, very similar in patients with stable angina and heart
transplant patients without and with posttransplant CAD, and 14.8- and
27.2-fold higher in patients with unstable angina and AMI, respectively
(Table 1
Plasma levels of C-reactive protein were 0.34±0.033 mg/dL in control
subjects, similar in patients with stable CAD and heart transplant
patients without and with posttransplant CAD, and 5.3- and 6.5-fold
higher in patients with unstable angina and AMI, respectively (Table 1
Plasma levels of D-dimer were 13±0.86 µg/dL in control
subjects, similar in patients with stable angina and heart transplant
patients without and with posttransplant CAD, 2.8-fold higher in
patients with unstable angina, and 4.4-fold higher in AMI patients
(Table 1
Multiple regression analysis was performed to evaluate the
association between angiographically detected CAD and plasma levels of
oxidized LDL and MDA-modified LDL. The analysis contained 144
patients without CAD (65 control subjects and 79 heart transplant
patients with angiographically normal coronary arteries) and
126 individuals with CAD. After correction for age, sex, LDL
cholesterol, and HDL cholesterol, CAD was
associated with elevated plasma levels of oxidized LDL
(r2=0.57; P=0.0001) and, to a
lesser extent, elevated plasma levels of MDA-modified LDL
(r2=0.26; P=0.0001). Multiple
regression analysis was performed on the subgroups of CAD
patients to study the association between acute coronary
syndromes and plasma levels of oxidized LDL and MDA-modified LDL. The
analysis contained 63 patients with stable CAD (35
nontransplanted and 28 transplanted patients) and 63 patients with
acute coronary syndromes. Elevated plasma levels of
MDA-modified LDL were associated with acute coronary syndrome,
increased troponin I, and increased C-reactive protein but not with
increased D-dimer (Table 3
Figure 4
Different mechanisms for the oxidation of LDL have been proposed.
Copper ion–induced in vitro oxidation of LDL results in the release of
hydroperoxides that are converted to reactive aldehydes (eg, MDA and
4-hydroxynonenal).21 22 Interaction of these
aldehydes with lysine residues in the apolipoprotein B-100 moiety
renders the LDL more negatively charged, which results in a decreased
affinity for the LDL receptor and an increased affinity for scavenger
receptors.3 Endothelial cells,
monocytes, macrophages, lymphocytes, and smooth muscle cells
are all capable of enhancing the rate of metal ion–induced in vitro
oxidation of LDL,23 and different enzymes may be
involved.24 25 26 27 28 Myeloperoxidase, secreted by
activated phagocytes, may be a catalyst for the initiation of
lipid peroxidation in LDL independent of free metal
ions.29 Previously, we isolated oxidized LDL from
the plasma of patients with posttransplant CAD.8
The characteristics suggested that it did not originate from extensive
metal ion–induced oxidation of LDL but that it might be generated by
cell-associated oxidative enzymatic activity in the
arterial wall. Previously, it was demonstrated in animal
models that the oxidation of LDL indeed occurs in the
arterial wall and not in the
blood.17 18
The causal role of oxidized LDL is suspected but not
established.30 31 32 33 The observed association
between CAD and plasma levels of oxidized LDL, measured in a specific
ELISA, suggests that the assay may be a useful tool to investigate the
causal role of oxidized LDL in atherosclerotic
cardiovascular disease in a prospective study.
Previously, we have also isolated MDA-modified LDL from the plasma of
AMI patients.9 It was concluded that it did not
originate from extensive metal ion–induced oxidation of LDL but that
it may be generated by MDA released by oxidation of
arachidonic acid present in
LDL.34 35 36 Ischemic injury may result not
only in the activation of the
cyclooxygenase-dependent pathway of
prostaglandin synthesis in endothelial
cells37 but also in increased production
of F2-isoprostanes,
non–cyclooxygenase-derived
prostaglandin F2–like
compounds,38 39 that are strong inducers of
platelet activation. Activated platelets may then
produce large amounts of aldehydes, further enhancing the modification
of LDL. The present very significant association between plasma
levels of MDA-modified LDL and markers of necrosis (troponin I) or
inflammation (C-reactive protein) further supports the hypothesis that
the generation of MDA-modified LDL is associated with ischemic
injury rather than with the extent of coronary
atherosclerosis. The very low reactivity of the
monoclonal antibody mAb-1H11 with nonthrombotic atherosclerotic plaques
indeed suggests that MDA-modified LDL, in contrast with oxidized LDL,
is not released continuously from atherosclerotic plaques. Hammer et
al40 recently characterized a monoclonal
antibody, mAb-OB/O9, that is specific for LDL modified with aldehydes
that can be released by activated platelets. It may be used
to further investigate the role of activated platelets in
the oxidative modification of LDL.
In conclusion, the present study demonstrates the association
between elevated plasma levels of oxidized LDL and CAD clinically
expressed in stable CAD and acute coronary syndromes. Elevated
levels of MDA-modified LDL, however, are associated with acute
coronary syndrome. A prospective investigation of the role of
MDA-modified LDL and/or oxidized LDL in the progression of
coronary atherosclerosis and/or the development
of atherothrombosis appears to be warranted.
Received March 23, 1998;
revision received June 11, 1998;
accepted June 13, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Oxidized LDL and Malondialdehyde-Modified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The association
between oxidative modifications of LDL and coronary artery
disease (CAD) is suspected but not established. Therefore, the
association between plasma levels of oxidized LDL and malondialdehyde
(MDA)-modified LDL and acute coronary syndromes and stable CAD
was investigated.
Key Words: lipoproteins • coronary disease • angina • diagnosis • plaque
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subendothelial accumulation of foam cells
plays a key role in the initiation of
atherosclerosis.1 2 These foam
cells, which may be generated by the uptake of oxidized LDL and/or
malondialdehyde (MDA)-modified LDL by macrophages via scavenger
receptors,3 accumulate in fatty streaks that
evolve to more complex fibrofatty or atheromatous
plaques.4 Oxidized LDL may also be involved in
atherogenesis by inducing smooth muscle cell
proliferation5 and smooth muscle foam cell
generation.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients and Blood Sampling
A total of 270 individuals were studied: 63 consecutive patients
with acute coronary syndromes, 35 patients with stable CAD, 107
posttransplant patients, and 65 control subjects. Patients with
acute coronary syndromes had ischemic chest discomfort
with ST-segment elevation or depression of >0.5 mm or T-wave
inversion of >1 mm. In 45 patients, elevated creatine kinase
(CK)-MB levels (and 
3% of total CK) were present at entry or in
the samples taken at 6 to 8 hours after enrollment, indicating AMI. In
18 patients, no CK-MB elevations were found, and these patients were
classified as having unstable angina. Thirty-five patients with
angiographically documented CAD and no clinical signs of
ischemia within the previous month were considered to have
stable CAD. 
).
View this table:
[in a new window]
Table 1. Characteristics of Control Subjects, CAD Patients,
and Heart Transplant
Patients
LDL was isolated from pooled plasma of fasting normolipidemic
donors by density gradient
ultracentrifugation.13
MDA-modified and copper-oxidized LDL was prepared as described
elsewhere.14 15
An mAb-4E6–based ELISA was used for the quantification of
oxidized LDL in plasma.8 16 17 18 Plasma levels of
MDA-modified LDL were measured in an mAb-1H11–based
ELISA.9 Total cholesterol, HDL
cholesterol, and triglycerides were measured by
enzymatic methods (Boehringer Mannheim). LDL
cholesterol values were calculated with the Friedewald
formula. Troponin I levels were measured on a Beckman ACCESS
immunoanalyzer by use of commercially available monoclonal
antibodies (Sanofi). C-reactive protein levels were measured in a
commercial immunoassay (Boehringer), and plasma levels of
D-dimer were measured in ELISA as described
previously.19
Coronary arteries were collected from cardiac explants
and treated as described elsewhere.9 Sections
were developed with either mAb-4E6 or mAb-1H11 (final concentration, 1
µg/mL). Immunostaining of smooth muscle cells and
monocytes or macrophages was performed with a murine monoclonal
antibody against human 
-actin (clone 1A4; Sigma Chemical Co) or a
rat monoclonal antibody against the common leukocyte antigen/CD45
(clone 30F11.1; Pharmingen).
Control subjects and patients were compared by
nonparametric Kruskal-Wallis ANOVA followed by Dunnet's
multiple comparison test in the Prism statistical program (Graph Pad
Software). Plasma levels of oxidized LDL and MDA-modified LDL in
patients with normal or elevated levels of troponin I, C-reactive
protein, or D-dimer and in patients with and without
peripheral vascular disease were compared by the
Mann-Whitney test. Discontinuous parameters were compared
by 
2 analysis. Multiple regression
analysis, with SAS software, was performed to evaluate the
association between angiographically detected CAD (independent
variable) and oxidized LDL or MDA-modified LDL (response) after
controlling for age, sex, LDL cholesterol, and HDL
cholesterol; it was also used to study the interaction with
heart transplantation. For patients with angiographically confirmed
CAD, multiple regression analysis was performed to study the
association between acute coronary syndromes, troponin I,
C-reactive protein, or D-dimer (independent variables)
and oxidized LDL or MDA-modified LDL (response) after controlling for
age, sex, LDL cholesterol, and HDL
cholesterol.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Plasma levels of oxidized LDL were 0.71±0. 033 mg/dL (mean±SEM)
in 65 control subjects, 1.8-fold higher (P<0.01) in heart
transplant patients with angiographically normal coronary
arteries, 3.7-fold higher (P<0.001) in patients with stable
angina pectoris, 4.0-fold higher (P<0.001) in patients with
unstable angina pectoris, 4.8-fold higher (P<0.001) in
patients with AMI, and 3.5-fold higher (P<0.001) in
patients with posttransplant CAD (Figure 1). Plasma levels of oxidized LDL were
independent of sex but correlated with age (Figure 2). In individuals with CAD, however,
there was no correlation between plasma levels of oxidized LDL and age.
Plasma levels of total cholesterol, LDL
cholesterol, and triglycerides in control
subjects and patients were very similar, whereas HDL
cholesterol levels in nontransplanted CAD patients were
significantly lower than in control subjects and the other patient
groups (Table 1
). Plasma levels of oxidized LDL were independent of LDL
cholesterol levels but correlated inversely with HDL
cholesterol levels (Figure 2). Plasma levels of oxidized
LDL were very similar in 21 CAD patients with clinical evidence of
peripheral vascular disease and 105 patients without
peripheral vascular disease (3.11± 0.27 and 2.89±0.095
mg/dL, respectively).
View larger version (24K):
[in a new window]
Figure 1. Individual values of oxidized LDL and MDA-modified
LDL in control subjects; nontransplanted patients with stable angina
and unstable angina and AMI; and heart transplant patients without and
with posttransplant CAD.
View larger version (37K):
[in a new window]
Figure 2. Plasma levels of oxidized LDL and MDA-modified LDL
vs age, sex, LDL cholesterol, and HDL
cholesterol, respectively. ).
Plasma levels of MDA-modified LDL were independent of sex and LDL
cholesterol levels and correlated weakly with age (Figure 2). In individuals with CAD, however, there was no correlation between
plasma levels of MDA-modified LDL and age. Plasma levels of
MDA-modified LDL did not correlate with LDL cholesterol and
correlated weakly with HDL cholesterol (Figure 2). Plasma
levels of MDA-modified LDL were very similar in 21 CAD patients with
and 105 patients without clinical evidence of peripheral
vascular disease (0.96± 0.14 versus 0.73±0.042 mg/dL). ). At a cutoff value of 0.1 ng/mL, exceeding the
99th percentile of distribution in individuals
without CAD, 40 of 45 AMI patients (89%) had increased troponin I
levels compared with 10 of 18 patients with unstable angina (55%), 2
of 35 patients with stable CAD (5.7%), 2 of 28 patients with
posttransplant CAD (7.1%), and 2 of 144 individuals without CAD
(0.7%). In agreement with previously published
data,10 11 troponin I was found to be a marker of
acute coronary syndromes (Table 2). Plasma levels of oxidized LDL were
3.26±0.14 mg/dL in CAD patients with increased troponin I levels
compared with 2.66±0.11 mg/dL in CAD patients with normal troponin I
levels (P<0.01) (Figure 3).
Corresponding values of MDA-modified LDL were 1.10±0.061 and
0.54±0.039 mg/dL, respectively (P<0.0001) (Figure 3).
View this table:
[in a new window]
Table 2. Distribution of Troponin I, C-Reactive Protein, and
D-Dimer in Patients With Acute Coronary Syndromes, Patients
With Stable Angina, and Individuals Without
CAD
View larger version (37K):
[in a new window]
Figure 3. Plasma levels of oxidized LDL and MDA-modified LDL
in CAD patients with normal and elevated levels of troponin I,
C-reactive protein, and D-dimer, respectively. ). At a cutoff value of 0.5 mg/dL, 39 AMI patients (97%), 10
patients with unstable angina (56%), 5 patients with stable angina
(14%), 2 patients with posttransplant CAD (7.1%), and 2 individuals
without CAD (1.4%) had increased levels of C-reactive protein. In
agreement with previously published data,12
C-reactive protein was found to be a marker of acute coronary
syndromes (Table 2). Plasma levels of oxidized LDL were 3.21±0.14
mg/dL in CAD patients with increased levels of C-reactive protein
compared with 2.71±0.11 mg/dL in patients with normal levels
(P<0.01) (Figure 3). Corresponding values of MDA-modified
LDL were 1.05±0.059 and 0.55±0.043 mg/dL, respectively
(P<0.0001) (Figure 3). ). At a cutoff value of 40 µg/dL, 22 AMI patients (49%), 8
patients with unstable angina (44%), 11 patients with stable angina
(31%), 1 patient with posttransplant CAD (3.6%), and 1 individual
without CAD (0.7%) had increased plasma levels of D-dimer.
In agreement with earlier published data,20
D-dimer was found to be a marker of acute coronary
syndromes (Table 2). Plasma levels of oxidized LDL were 3.17±0.18
mg/dL in patients with increased D-dimer levels compared
with 2.81±0.10 mg/dL in patients with normal D-dimer
levels (P=NS). Corresponding values of MDA-modified LDL were
0.94±0.091 and 0.69±0.042 mg/dL, respectively (P<0.01)
(Figure 3). ).
Differences between plasma levels of oxidized LDL in patients with
stable CAD and patients with acute coronary syndromes were less
pronounced (Table 3). Plasma levels of oxidized LDL and MDA-modified
LDL were similar in nontransplanted and transplanted patients with
stable CAD.
View this table:
[in a new window]
Table 3. Multiple Regression Analysis of Association Between
Acute Coronary Syndromes and Plasma Levels of Oxidized LDL or
MDA-modified LDL shows
representative sections of coronary arteries
obtained from the cardiac explants of CAD patients. mAb-4E6
immunostained oxidized LDL in nonthrombotic human
coronary atherosclerotic plaques (Figure 4a, 4b, 4e, and 4f).
Oxidized LDL was associated with smooth muscle foam cells in the
fibrous cap (Figure 4b and 4f) and was present in the necrotic core
(not shown). In contrast, mAb-1H11 detected only very small amounts of
immunoreactive material associated with macrophages in the
shoulder areas (Figure 4d), whereas no immunoreactive material was
detected in the necrotic core of nonthrombotic plaques (Figure 4h).
View larger version (121K):
[in a new window]
Figure 4. Representative sections of
coronary arteries isolated from cardiac explants of patients
with end-stage ischemic heart disease. mAb-4E6
immunostained oxidized LDL in nonthrombotic human
coronary atherosclerotic plaques (a, b, e, f). Oxidized LDL was
associated with smooth muscle foam cells (immunostained
with cell-specific mAb-1A4) in fibrous cap (b, f) or was present in
necrotic core (not shown). In contrast, mAb-1H11 detected only very
small amounts of immunoreactive material in nonthrombotic
atherosclerotic lesions (c, d, g, h). Immunostaining
was associated with macrophage foam cells
(immunostained with cell-specific mAb-30F11) in shoulder
areas (d) or was absent (h).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study demonstrates that plasma levels of oxidized
LDL are significantly elevated in CAD patients and that these levels
are very similar in patients with stable CAD and in patients with acute
coronary syndromes, suggesting that their increases are
independent of plaque instability. The presence of oxidized LDL in
nonthrombotic plaques and the lack of correlation between plasma levels
of oxidized LDL and LDL cholesterol suggest that increased
plasma levels of oxidized LDL in association with CAD may be due to
their back-diffusion from the vessel wall. In contrast, plasma levels
of MDA-modified LDL were significantly higher in patients with acute
coronary syndromes than in patients with stable CAD, suggesting
that increases in plasma levels of MDA-modified LDL are dependent on
the ischemic syndromes in patients with unstable angina
pectoris or AMI. The association between MDA-modified LDL and troponin
I, a marker of ischemic syndromes, further supports this
hypothesis. Furthermore, the increase in MDA-modified LDL was
associated more with inflammation (with C-reactive protein as marker)
than with thrombotic syndromes (with D-dimer as marker).
These data thus suggest that elevated levels of MDA-modified LDL may be
markers of plaque instability.
Acknowledgments
This work was supported in part by a grant from the Nationaal
Fonds voor Geneeskundig Wetenschappelijk Onderzoek (project
3.0103.92) and by the Interuniversitaire Attractiepolen (Program 4/34).
Dr Vanhaecke holds the Michael Ondetti Chair in
Cardiology. We are grateful to Drs W. Daenen, W.
Flameng, and P. Sergeant for providing coronary arteries of the
cardiac explants; to H. Bernar and M. Landeloos for technical
assistance; and to Dr K. Bogaerts of the Biostatistical Center for
Clinical Trials, University of Leuven, for statistical
analysis. We thank K. Roels (Analis, Gent, Belgium) for
measuring levels of troponin I.
Footnotes
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-417).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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 T. Wu, W. C. Willett, N. Rifai, I. Shai, J. E. Manson, and E. B. Rimm Is Plasma Oxidized Low-Density Lipoprotein, Measured With the Widely Used Antibody 4E6, an Independent Predictor of Coronary Heart Disease Among U.S. Men and Women? J. Am. Coll. Cardiol., September 5, 2006; 48(5): 973 - 979. [Abstract] [Full Text] [PDF]
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G. N. Fredrikson, G. Berglund, R. Alm, J.-A. Nilsson, P. K. Shah, and J. Nilsson Identification of autoantibodies in human plasma recognizing an apoB-100 LDL receptor binding site peptide J. Lipid Res., September 1, 2006; 47(9): 2049 - 2054. [Abstract] [Full Text] [PDF]
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 N. Duerrschmidt, O. Zabirnyk, M. Nowicki, A. Ricken, F. A. Hmeidan, V. Blumenauer, J. Borlak, and K. Spanel-Borowski Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1-Mediated Autophagy in Human Granulosa Cells as an Alternative of Programmed Cell Death Endocrinology, August 1, 2006; 147(8): 3851 - 3860. [Abstract] [Full Text] [PDF]
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P. Castilla, R. Echarri, A. Davalos, F. Cerrato, H. Ortega, J. L. Teruel, M. F. Lucas, D. Gomez-Coronado, J. Ortuno, and M. A Lasuncion Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects Am. J. Clinical Nutrition, July 1, 2006; 84(1): 252 - 262. [Abstract] [Full Text] [PDF]
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 D. Macut, S. Damjanovic, D. Panidis, N. Spanos, B. Glisic, M. Petakov, D. Rousso, A. Kourtis, J. Bjekic, and N. Milic Oxidised low-density lipoprotein concentration - early marker of an altered lipid metabolism in young women with PCOS. Eur. J. Endocrinol., July 1, 2006; 155(1): 131 - 136. [Abstract] [Full Text] [PDF]
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B. Mackness, R. Quarck, W. Verreth, M. Mackness, and P. Holvoet Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1545 - 1550. [Abstract] [Full Text] [PDF]
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