© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Antibodies to Oxidized LDL in Relation to Intima-Media Thickness in Carotid and Femoral Arteries in 58-Year-Old Subjectively Clinically Healthy Men
From The Wallenberg Laboratory for Cardiovascular Research (J.H.) and the Department of Medicine (L.B., B.F.), Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden.
Correspondence to Johannes Hulthe, MD, PhD, The Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden. E-mail johannes.hulthe{at}wlab.wall.gu.se
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Antibody (Ab) titers to oxidized low density lipoprotein (OxLDL) have been found to be independent predictors of the progression of carotid atherosclerosis. Ab titers against OxLDL may be related to the entire burden of atherosclerosis in the vascular tree or, more specifically, to the disease process in different arterial regions. Therefore, the aim of the present study was to investigate the relationship between IgG and IgM titers to modified LDL and intima-media thickness (IMT) in the carotid and femoral arteries in subjectively clinically healthy 58-year-old men. IMT was measured by ultrasound, and Ab titers to modified LDL were measured by ELISA. The results showed that the common carotid artery IMT was associated with elevated titers of IgG-OxLDL Ab and independently with systolic blood pressure, smoking, and body mass index. The femoral artery IMT showed a negative correlation to IgM-OxLDL Ab and independent associations with smoking, systolic blood pressure, and total cholesterol. To summarize, in 58-year-old subjectively clinically healthy men recruited from the general population, there was a positive association between IgG-OxLDL Ab and IMT in the common carotid artery and a negative association between IgM-OxLDL Ab and IMT in the common femoral artery. However, these associations were not independent of other risk factors.
Key Words: antibody • oxidized LDL • intima-media thickness
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Immune mechanisms have been suggested to play a key role in the development of atherosclerosis.1 Several lines of evidence support the possibility that oxidized LDL (OxLDL) may be a key antigen in atherosclerosis. T-cell clones responsive to OxLDL have been isolated from human lesions.2 Immune responses to OxLDL have also been observed in apoE knockout mice, an animal model for the development of atherosclerosis.3 Furthermore, antibodies (Abs) against epitopes of OxLDL have been found in several studies in human4 5 and rabbit4 5 6 plasma and in atherosclerotic lesions. So far, it has not been established whether the immune responses to OxLDL are proatherogenic or antiatherogenic in vivo.7 8
There are case-control studies suggesting an elevated Ab titer against OxLDL in patients with various manifestations of atherosclerotic disease.9 10 11 12 13 High titers of Abs have also been found to be independent predictors of the progression of carotid atherosclerosis.14 In other recent studies, however, no such relationships have been found between atherosclerotic disease and Ab titers.15 16 17 In 2 recent studies, a reduction of OxLDL Abs was reported in patients with ischemic stroke18 and in patients with acute myocardial infarction.19
Measurements of IMT are used in pathophysiological studies of the atherosclerotic process, eg, in studies of the factors regulating the early development of atherosclerosis in the carotid and femoral arteries. An increased IMT is also used as a marker of generalized atherosclerosis, including coronary atherosclerosis,20 21 and carotid artery IMT has also been shown to be associated with coronary atherosclerosis, as measured by coronary angiography in several studies.22 23 However, the mechanisms involved in the atherosclerotic process may not be identical in different vascular territories. Thus, myocardial infarction, stroke, and peripheral artery disease have slightly different cardiovascular risk factor profiles; eg, cholesterol is a strong risk factor for myocardial infarction, whereas the association with stroke and intermittent claudication is weak or inconsistent.24 Hypothetically, the level of circulating Abs against OxLDL may be related to the entire burden of atherosclerosis in the vascular tree or, more specifically, to the disease process in specific arterial regions.
Therefore, the aim of the present study was to investigate the relationship between Ab titers (IgG and IgM) to modified LDL and IMT in the carotid and femoral arteries in 58-year-old healthy subjects recruited from the general population.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Subjects
The inclusion criteria were age 58 years, male sex, and Swedish ancestry. Exclusion criteria were cardiovascular or other clinically overt disease (eg, malignancy or psychiatric disease), continuous medication with cardiovascular drugs (ie, antidiabetic, lipid-lowering, antihypertensive, or heart failure–related drugs or drugs for angina pectoris) that might disturb the measurements performed in the study, or unwillingness to participate. The subjects were randomly selected among men in the County Council register and were invited to a screening examination.25
A power calculation indicated that it was necessary to recruit at least 300 men in the study, with the main objective being to examine the relationship between insulin sensitivity and ultrasound-assessed atherosclerosis. The present report is a substudy of that project.
The subjects received written and oral information before they gave their consent to participate. The study was approved by the ethics committee at Sahlgrenska University Hospital.
Measurements
All measurements were performed in the morning.
Venous blood samples were drawn after a fasting period of 10 to 12
hours, and serum was separated and frozen within 4 hours at -70°C.
Body weight, height, waist, and hip circumference were measured, and
body mass index (BMI) and the waist-to-hip ratio (WHR) were
calculated.
Information on general health and smoking habits was obtained by a self-administered questionnaire. The total number of years of smoking was multiplied by the number of cigarettes smoked daily. The product was called "cigarette-years."
Ab Titers Against Modified Lipoproteins
Lipoprotein Preparation
LDL (1.019 to 1.063 g/mL) was prepared from pooled
plasma from 2 healthy human donors by sequential
ultracentrifugation in the presence of 0.2%
Na2-EDTA. The isolated lipoprotein was
extensively dialysed against PBS (0.14 mol/L NaCl/0.01 mol/L PBS)
containing 0.1 mmol/L Na2-EDTA, 2.5
µL 0.4 mol/L AEBSF, and 5 mL penicillin/streptomycin per liter
(pH 7.4). LDL was sterilely filtered, and the protein content was
determined by the method of Lowry et
al.26 Malondialdehyde
(MDA)-treated LDL (MDA-LDL) was prepared as described by Palinski et
al.27 OxLDL was prepared by
oxidation of LDL in the presence of 5 mmol/L
CuSO4 for 13 hours at
37°C.28 As a routine
procedure, modifications were checked by controlling the
electrophoretic mobility in agarose gel of the modified
lipoproteins.
Determination of Ab Titers Against Modified
Lipoproteins
Ab titers were determined with a solid-phase ELISA,
as earlier described.29 Ab
titer was defined as follows: titer=absorbance (patient
serum-postcoat)/(internal Ab titer standard
serum-postcoat).
For IgG, the postcoated wells gave no absorbance; therefore, this correction was made only for IgM.
Internal Ab Titer Standard Used
On each plate, 2 different internal standard serum
samples were repeatedly performed. The absorbances for these 2 samples,
named internal control sample (ICS) and internal standard sample (ISS),
were used to calculate the ratio of ICS to ISS, which was used as the
internal Ab titer standard. When earlier described predefined criteria
for reanalyzing Ab titers were used, the variability has been shown to
be satisfactory.29 SDs for
the mean value of the ratio of ICS to ISS (ie, internal Ab titer
standard used) from all plates were 0.07 and 0.03 for IgG titers
against OxLDL (IgG-OxLDL Ab) and MDA-LDL (IgG-MDA-LDL Ab),
respectively, and 0.06 and 0.06 for IgM titers against OxLDL (IgM-OxLDL
Ab) and MDA-LDL (IgM-MDL-LDL Ab), respectively, when the predefined
criteria were used.
Ultrasonography: IMT
Examination was performed by use of an ultrasound
scanner (Acuson 128) with a 7-MHz linear transducer aperture of 38
mm. The ECG signal (lead II) was simultaneously
recorded to synchronize the image capture of the top of the R wave
to minimize variability during the cardiac cycle. The left and right
carotid arteries were scanned at the level of the bifurcation, and
images for IMT measurements were recorded from the far wall in the
common carotid artery and the carotid artery bulb and from the right
femoral artery. The software program gives the average thickness of the
intima-media complex (ie, the IMT). Measurements in the common femoral
artery were made in a manner similar to that for the carotid artery but
along a 15-mm-long section proximal to the
bifurcation.30 IMT was
defined as the distance from the leading edge of the lumen-intima
interface to the leading edge of the media-adventitia interface of the
far wall. At the position of the thickest part of the wall (visually
judged), a frozen longitudinal image was captured and recorded on
videotape. A short sequence of real-time images was also recorded
on videotape to assist in the interpretation of the frozen images. The
images were measured in an automated analyzing
system,31 which was based on
automatic detection of the echo structures in the ultrasound image but
with the option of making manual corrections by the operator. The
interobserver variations for IMT have been shown to be
satisfactory.32
The present analysis used the average of measurements of IMT from the left and right common carotid arteries (common carotid artery and carotid bulb).
Biochemical Analysis
Cholesterol and triglyceride
levels were determined by fully enzymatic
techniques.33 34
HDL was determined after precipitation of apoB-containing lipoproteins
with Mn-chloride and dextran sulphate. LDL cholesterol was
calculated as described by Friedewald et
al.35 Blood glucose was
measured with the glucose oxidase technique. Plasma insulin was
determined in all subjects with a radioimmunoassay (Pharmacia Insulin
RIA, Pharmacia Diagnostics). All lipid analyses
were performed at the Wallenberg Laboratory.
Statistical Analysis
All statistics were analyzed by using SPSS
for Windows 8.0. A nonparametric Spearman rank correlation
test was used in the correlation analysis, with the
relationship illustrated by the Pearson correlation coefficient
(r). The Mantel test for linear
association was used to test the relationship between tertiles of
common carotid IMT and the variables displayed in
Tables 1
and 2.
The Mantel test and the Mann-Whitney test were used when investigating
the relationship between tertiles of Ab titers against OxLDL and IMT in
the common carotid and common femoral arteries. A stepwise multiple
regression model was used to study the determinants of IMT in the
carotid and femoral arteries. Triglyceride was
logarithmically transformed for statistical testing to improve
skewness. A value of P<0.05
(2-sided) was regarded as statistically significant, with the exception
of the correlations between IMT and cardiovascular risk
factors. Because of the large number of correlations performed, the
significance level for these analyses was set at
P
0.01. For anatomic reasons,
there were missing data for common carotid and femoral artery IMT
measurements (n=3 and n=18, respectively). For technical reasons, there
were also missing data for Ab titers in 8
cases.
|
|
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Characteristics of Subjects by Tertiles of Common Carotid Artery IMT
No subject had clinically recognized diabetes mellitus. Blood glucose
6.1 mmol/L was found in 22 subjects. When the
subjects were divided into tertiles on the basis of IMT in the common
carotid artery, there were positive trends between IMT and BMI, WHR,
systolic and diastolic blood pressure, total
cholesterol, LDL cholesterol,
triglycerides, blood glucose, and smoking
(Table 1
). There was a significant positive trend between
IMT and IgG-OxLDL Ab.
Characteristics of Subjects by Tertiles of
Common Femoral Artery IMT
When the subjects were divided into tertiles on the
basis of IMT in the common femoral artery, there were positive trends
between IMT and BMI, WHR, systolic and diastolic
blood pressure, heart rate, total cholesterol, LDL,
triglycerides, and smoking
(Table 2). There was a negative trend between IMT and
IgM-OxLDL Ab
(P=0.050).
The common carotid artery IMT was associated with the femoral artery IMT (r=0.22, P<0.001).
Covariates to IMT in the Common Carotid and
Common Femoral Arteries
In the correlation analyses, IgG-OxLDL Abs were
significantly associated with IMT in the common carotid artery
(r=0.13,
P<0.01). IgM-MDA-LDL Abs were
negatively associated with IMT in the in the common femoral artery
(r=-0.10,
P<0.05).
When the subjects were divided on the basis of IgG-Ox-LDL Ab
titer, there was a positive relationship between IMT in the common
carotid artery and increasing Ab titer
(Figure 1). In the femoral artery, there was a negative
relationship between IMT and tertiles on the basis of IgM-OxLDL Ab
titer
(Figure 2).
|
|
The Ab titers showed high intercorrelations for IgG (IgG-OxLDL Ab versus IgG-MDA-LDL Ab, r=0.75 and P<0.001) and for IgM titers (IgM-OxLDL Ab versus IgM-MDA-LDL Ab, r=0.91 and P<0.001). The IgG-OxLDL Ab and IgM-MDA-LD Ab titers were significantly and negatively correlated (r=-0.10, P<0.05).
As shown in
Table 3, BMI, WHR, systolic and
diastolic blood pressure, triglycerides,
cigarette-years, and IgG- OxLDL Abs were significantly associated
with IMT in the common carotid artery
(P<0.01). Correspondingly,
WHR, systolic and diastolic blood pressure, heart
rate, total cholesterol, LDL cholesterol, HDL
cholesterol, triglycerides, and cigarette-years
were significantly associated with IMT in the common femoral artery
(P<0.01).
|
In a multiple regression analysis with the common
carotid artery IMT as a dependent variable and the variables
significantly associated with IMT
(Table 3), systolic blood pressure (F value 42.7),
cigarette-years (F value 30.1), and BMI (F value 22.9) turned out to be
independent predictors (adjusted
R2=0.15)
of common carotid IMT. Correspondingly, the common femoral artery IMT
was independently associated with cigarette-years (F value 78.9),
systolic blood pressure (F value 45.0), and total
cholesterol (F value 32.9). Adjusted
R2
for the model was 0.21.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The results of the present study showed that the common carotid artery IMT was associated with elevated titers of IgG Abs to OxLDL and independently with systolic blood pressure, smoking, and BMI. The femoral artery IMT did not show any statistically significant associations with the IgG Abs but a negative correlation to the IgM Ab titer of OxLDL and independent associations with smoking, systolic blood pressure, and total cholesterol.
We studied serum titers of different types of Abs to modified LDL in venous blood drawn from an antecubital vein. It is reasonable to assume that the observed titers reflect an overall immune response, necessitating knowledge of atherosclerosis in several vascular sites. We assessed IMT in 2 of the most prevalent sites for the atherosclerotic process, ie, the carotid and femoral arteries. In concordance with previous reports, it was found that IMT, as a measure of atherosclerosis, was associated with many established risk factors for cardiovascular disease, with smoking as the most important factor in the femoral artery and systolic blood pressure as the most important factor in the carotid artery.36 37 When the Ab titers to modified LDL were examined, the pattern that emerged was that elevated titers of IgG Abs to OxLDL were positively associated with IMT in the carotid artery, whereas the IgM Ab to OxLDL was inversely associated with IMT in the femoral artery. The data from the present cross-sectional study do not allow an interpretation of a difference in the immune response between the carotid and femoral arteries. However, the reverse relationship between the IgG and IgM Abs versus ultrasound-assessed atherosclerosis is also supported by the negative association between IgG and IgM Ab titers. Our interpretation of the results is that IgG Abs to OxLDL accompanied the atherosclerotic process, whereas the IgM Abs showed a reversed response. These associations were not independent of established risk factors for atherosclerotic disease.
To our knowledge, this is the first study that has examined the relationship between different Abs to modified LDL and different vascular territories in subjectively clinically healthy subjects recruited from the general population. In a previous study using ultrasound examinations of the carotid and femoral arteries of hypertensive subjects, a positive association was found between autoantibodies against OxLDL and MDL-LDL and carotid IMT in patients without atherosclerotic plaques.38
We studied 58-year-old, white, untreated men of Swedish ancestry who were chosen to minimize the effect of confounding factors such as race, ethnicity, sex, age, and treatment with different drugs for cardiovascular disease. We believe that eliminating these factors enhanced the possibility of studying the relationship between IMT and Ab titers and modified LDL. The limitation is that women were not examined and that there was a stratified selection related to the degree of estimated insulin sensitivity. However, the relationship between cardiovascular risk factors and measured IMT followed the expected pattern.
OxLDL is believed to act as a driving antigen in the complicated immune response to atherosclerosis.7 It has been hypothesized that Ab titers to OxLDL may reflect the LDL Ab level and therefore confer important information. Some studies have reported results supporting such a concept.9 12 Circulating Abs against OxLDL have also been suggested to be an independent predictor for IMT progression in the carotid artery.14 The data from the present study showing a positive relationship between IMT in the common carotid artery and IgG-OxLDL Abs corroborate these earlier studies (eg, that the IgG response to modified LDL is proatherogenic).
However, it may also be postulated that the physiological function of Abs to OxLDL and related compounds is to participate in the removal of these agents from the artery wall and to have a protective role (eg, an antiatherogenic role of the humoral immune system), similar to the defense mechanisms in infectious disease. In support of the concept that the immune response might be antiatherogenic rather than proatherogenic are recent reports that have indicated that immunization of experimental animals with OxLDL leads to dramatically enhanced IgG levels and inhibits the progression of atherosclerosis.39 40 41 A published study indicated that low Ab levels may be associated with more pronounced atherosclerotic disease.42 In a previous study in our laboratory, we showed that subjects with familial hypercholesterolemia and previous myocardial infarction had significantly lower IgM titers compared with titers in subjects with familial hypercholesterolemia without previous myocardial infarction but also compared with titers in control subjects.29
We observed that contrary to IgG-OxLDL Abs, IgM- OxLDL Abs were lower in subjects with a thick intima-media complex in the common femoral artery. The discrepancy relating to the above-mentioned findings could be due to different Ab responses in different stages of the atherosclerotic process or to different responses in different segments of the vessel wall. The present study does not give any information on underlying mechanisms. However, on basis of earlier studies, one might also speculate that the immune system has a partly protective role. As suggested by Hansson,7 the adaptive immune system appears to inhibit certain aspects of atherosclerosis, eg, smooth muscle cell proliferation and scavenger receptor expression, whereas other important components are enhanced, such as macrophage activation and protease secretion. A protective role of the humoral immune response is suggested by the animal studies mentioned above and in 1 recent study, in which where Nicoletti et al43 found that a spleen-associated immune response could protect against atherosclerosis in apoE-deficient mice. B cells can produce IgM without T-cell help, and the high titer of IgM to OxLDL in the present study may reflect T-cell–independent B-cell activation.44
To summarize, in 58-year-old subjectively clinically healthy men recruited from the general population, there was a positive association between IgG-OxLDL Ab and IMT in the common carotid artery and a negative association between IgM-OxLDL Ab and IMT in the common femoral artery. However, these associations were not independent of other risk factors, such as metabolic variables and smoking.
|
Acknowledgments |
|---|
This work was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (12270 and 10880), the King Gustav V and Queen Viktoria Foundation, and Astra Zeneca Mölndal, Sweden. We thank laboratory technologists Eva-Lena Alenhag, Anna Frödén, Caroline Schmidt, and Aira Lidell For excellent research assistance.
Received April 6, 2000; accepted August 18, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Hansson GK. Immune responses in atherosclerosis. In: Hansson GK, Libby P, eds. Immune Functions of the Vessel Wall. Amsterdam, Netherlands: Harwood Academic Publishers; 1996. [Vadas M, Harlan JM, eds. Advances in Vascular Biology.]>
2.
Stemme S, Faber B,
Holm J, Bondjers G, Witztum JL, Hansson GK. T lymphocytes from human
atherosclerotic plaques recognize oxidized low density lipoprotein.
Proc Natl Acad Sci
U S A. 1995;92:3893–3897.
3. Palinski W, Hörkkö S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK, Witztum JL. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice: demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996;98:800–814.[Medline] [Order article via Infotrieve]
4.
Ylä-Herttuala S,
Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL. Rabbit and
human atherosclerotic lesions contain IgG that recognizes epitopes of
oxidized LDL. Arterioscler
Thromb. 1994;14:32–40.
5.
Palinski W,
Rosenfeld ME, Ylä-Herttuala S, Gurtner GC, Socher SS, Butler SW,
Parathasarathy S, Carew TE, Steinberg D, Witztum JL. Low density
lipoprotein undergoes oxidative modification in vivo.
Proc Natl Acad Sci
U S A. 1989;86:1372–1376.
6.
Rosenfeld ME,
Palinski W, Ylä-Herttuala S, Butler S, Witztum JL. Distribution of
oxidation specific lipid protein adducts and apolipoprotein B in
atherosclerotic lesions of varying severity from WHHL rabbits.
Arteriosclerosis. 1990;10:336–349.
7. Hansson GK. Cell-mediated immunity in atherosclerosis. Curr Opin Lipidol. 1997;8:301–311.[Medline] [Order article via Infotrieve]
8. Witzum JL. Immunological response to oxidized LDL. Atherosclerosis. 1997;131:S9–S11.
9. Bui M, Sack M, Moutsatsos G, Lu D, Katz P, Mc Cown R, Breall J, Rackley C. Autoantibody titers to oxidized low-density lipoprotein in patients with coronary atherosclerosis. Am Heart J. 1996;131:663–667.[Medline] [Order article via Infotrieve]
10. Maggi E, Marchesi E, Ravetta V, Martignoni A, Finardi G, Bellomo G. Presence of autoantibodies against oxidatively modified low-density lipoprotein in essential hypertension: a biochemical signature of an enhanced in vivo low-density lipoprotein oxidation. J Hypertens. 1995;13:129–138.[Medline] [Order article via Infotrieve]
11.
Bergmark C, Wu R,
de Faire U, Lefvert AK, Swedenborg J. Patients with early-onset
peripheral vascular disease have increased levels of
autoantibodies against oxidized LDL.
Arterioscler Thromb Vasc Biol. 1995;15:441–445.
12.
Puurunen M,
Manttari M, Manninen V, Tenkanen L, Alfthan G, Ehnholm C, Vaarala O,
Aho K, Palosuo T. Antibody against oxidized low-density lipoprotein
predicting myocardial infarction. Arch
Intern Med. 1994;154:2605–2609.
13. Chiesa R, Melissano G, Castellano R, Astore D, Marone EM, Grossi A, Maggi E, Finardi G, Casasco A, Bellomo G. In search of biological markers of high-risk carotid artery atherosclerotic plaque: enhanced LDL oxidation. Ann Vasc Surg. 1998;12:1–9.[Medline] [Order article via Infotrieve]
14. Salonen JT, Ylä-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyssönen K, Palinski W, Witztum JL. Autoantibodies against oxidized LDL and progression of carotid atherosclerosis. Lancet. 1992;339:883–887.[Medline] [Order article via Infotrieve]
15.
Uusitupa M,
Niskanen L, Luoma J, Vilja P, Mercuri M, Rauramaa R, Ylä-Herttuala S.
Autoantibodies against oxidized LDL do not predict atherosclerotic
vascular disease in non-insulin-dependant diabetes mellitus.
Arterioscler Thromb Vasc Biol. 1996;16:1236–1242.
16. Van de Vijer L, Steyger R, Poppel G, Boer J, Kruijssen D, Seidell J, Princen H. Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls. Atherosclerosis. 1996;122:245–253.[Medline] [Order article via Infotrieve]
17.
Iribarren C,
Folsom AR, Jacobs DR Jr, Gross MD, Belcher JD, Eckfeldt JH. Association
of serum vitamin levels, LDL susceptibility to oxidation, and
autoantibodies against MDA-LDL with carotid
atherosclerosis: a case-control study: the ARIC Study
Investigators:. Atherosclerosis Risk in Communities.
Arterioscler Thromb Vasc Biol. 1997;17:1171–1177.
18. Cherubini A, Mecocci P, Senin U. Autoantibodies against oxidized low-density lipoproteins in older stroke patients. J Am Geriatr Soc. 1997;45:125.
19. Schumacher M, Eber B, Tatzber F, Kaufmann P, Halwachs G, Fruhwald FM, Zweiker R, Esterbauer H, Klein W. Transient reduction of autoantibodies against oxidized LDL in patients with acute myocardial infarction. Free Radic Biol Med. 1995;18:1087–1091.[Medline] [Order article via Infotrieve]
20.
Wikstrand J,
Wiklund O. Frontiers in cardiovascular science:
quantitative measurements of atherosclerosis
manifestations in humans. Arterioscler
Thromb. 1992;12:114–119.
21. Grobbee DE, Bots ML. Carotid intima-media thickness as an indicator of generalized atherosclerosis. J Intern Med. 1994;236:567–573.[Medline] [Order article via Infotrieve]
22.
Adams MR, Nakagomi
A, Keech A, Robinson J, McCredie R, Bailey BP, Feedman SB, Celermajer
DS. Carotid intima-media thickness is only weakly related with the
extent and severity of coronary artery disease.
Circulation. 1995;92:2127–2134.
23.
Hulthe J,
Wikstrand J, Emanuelsson H, Wiklund O, de Feyter P, Wendelhag I.
Atherosclerotic changes in the carotid artery bulb as measured by
B-mode ultrasound are associated with the extent of coronary
atherosclerosis.
Stroke. 1997;28:1189–1194.
24. Criqui MH, Langer RD, Fronek A, Feigelson, Klauber MR. Large vessel and isolated small vessel disease. In: Fowkes FGR, ed. Epidemiology of Peripheral Vascular Disease. London, UK: Springer Verlag; 1991:85–96.
25.
Hulthe J, Bokemark
L, Wikstrand J, Fagerberg B. The metabolic syndrome, LDL
particle size, and atherosclerosis: the
Atherosclerosis and Insulin Resistance (AIR) Study.
Arterioscler Thromb Vasc Biol.. 2000;20:2140–2147.
26. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:1831–1841.
27.
Palinski W,
Ylä-Herttuala S, Rosenfeld ME, Butler SW, Socher SA, Parthasarathy S,
Curtiss LK, Witzum JL. Antisera and monoclonal antibodies specific for
epitopes generated during oxidative modification of low density
lipoproteins.
Arteriosclerosis. 1990;10:325–335.
28. Regnström J, Walldius G, Carlsson L, Nilsson J. Effect of probucol treatment on the susceptibility of low density protein isolated from hypercholesterolemic patients to become oxidatively modified in vitro. Atherosclerosis. 1990;82:43–51.[Medline] [Order article via Infotrieve]
29.
Hulthe J,
Wikstrand J, Lidell A, Wendelhag I, Hansson GK, Wiklund O. Antibody
titers against oxidized LDL are not elevated in patients with familial
hypercholesterolemia.
Arterioscler Thromb Vasc Biol. 1998;18:1203–1211.
30.
Wendelhag I,
Wiklund O, Wikstrand J. Atherosclerotic changes in the femoral and
carotid arteries in familial
hypercholesterolemia: ultrasonographic
assessment of intima-media thickness and plaque occurrence.
Arterioscler Thromb. 1993;13:1404–1411.
31.
Wendelhag I, Liang
Q, Gustavsson T, Wikstrand J. A new automated computerized analyzing
system simplifies readings and reduces the variability in ultrasound
measurement of intima-media thickness.
Stroke. 1997;28:2195–2200.
32. Schmidt C, Wendelhag I. How can the variability in ultrasound measurement of intima-media thickness be reduced?: studies of interobserver variability in carotid and femoral arteries. Clin Physiol. 1999;1:45–55.
33. Klose S, Borner K. Enzymatische Bestimmung des Gesamtcholesterins mit dem Greiner Selective Analyzer (GSA-II). J Clin Chem Clin Biochem. 1978;15:121–130.
34. Wahlefeld AW. Triglycerides. determination after enzymatic hydrolysis. In: Bermeyer HU, ed. Methods of Enzymatic Analysis. 2nd English ed. New York, NY: Academic Press Inc; 1974:18–31.
35. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
36. Poli L, Zanocchi M, Bo M, Fonte G, Fabris F. Risk factors for atherosclerosis: ultrasound evaluation of carotid and femoral arteries in patients examined by coronary angiography. Int Angiol. 1993;12:13–20.[Medline] [Order article via Infotrieve]
37. Joensuu T, Salonen R, Winblad I, Korpela H, Salonen JT. Determinants of femoral and carotid artery atherosclerosis. J Intern Med. 1994;236:79–84.[Medline] [Order article via Infotrieve]
38. Marchesi E, Martignoni A, Salvini M, Catalano O, Maggi E, Negro C, Traversa-B, Bellomo G. Carotid intima-media thickening and in vivo LDL oxidation in patients with essential hypertension. J Hum Hypertens. 1996;10:577–582.[Medline] [Order article via Infotrieve]
39.
Palinski W, Miller
E, Witztum JL. Immunization of low density lipoprotein (LDL)
receptor-deficient rabbits with homologous malondialdehyde modified LDL
reduces atherogenesis. Proc Natl Acad Sci
U S A. 1995;92:821–825.
40.
Ameli S,
Hultgårdh-Nilsson A, Regnström J, Calara F, Yano J, Cervek B, Shah
PK, Nilsson J. Effect of immunization with homologous LDL and oxidized
LDL on early atherosclerosis in
hypercholesterolemic rabbits.
Arterioscler Thromb Vasc Biol. 1996;16:1074–1079.
41. Nilsson J, Calara F, Regnström J, Hultgardh-Nilsson A, Ameli S, Cercek B, Shah PK. Immunization with homologous oxidized low density lipoprotein reduces neointimal formation after balloon injury in hypercholesterolemic rabbits. J Am Coll Cardiol. 1997;30:1886–1891.[Abstract]
42.
Ruihua W, de Faire
U, Lemne C, Witztum J, Frostegård J, Autoantibodies to OxLDL are
decreased in individuals with borderline hypertension.
Hypertension. 1999;33:53–59.
43. Nicoletti A, Caliguri G, Hansson GK. Reduction of atherosclerosis by adoptive transfer of protective immunity in apoE knockout mice. Eur Heart J. 1999;20(suppl):607.
44. Palinski W, Hörkkö S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK, Witztum JL. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from lipoproteins form apolipoprotein E-deficient mice: demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996;98:800–814.
This article has been cited by other articles:
 |
|
 |
|
  M. Sampi, O. Ukkola, M. Paivansalo, Y. A. Kesaniemi, C. J. Binder, and S. Horkko Plasma Interleukin-5 Levels Are Related to Antibodies Binding to Oxidized Low-Density Lipoprotein and to Decreased Subclinical Atherosclerosis J. Am. Coll. Cardiol., October 21, 2008; 52(17): 1370 - 1378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Binder, K. Hartvigsen, and J. L. Witztum Promise of Immune Modulation to Inhibit Atherogenesis J. Am. Coll. Cardiol., August 7, 2007; 50(6): 547 - 550. [Full Text] [PDF]
|
|
|
|
 |
|
 G. N. Fredrikson, B. Hedblad, G. Berglund, R. Alm, J.-A. Nilsson, A. Schiopu, P. K. Shah, and J. Nilsson Association Between IgM Against an Aldehyde-Modified Peptide in Apolipoprotein B-100 and Progression of Carotid Disease Stroke, May 1, 2007; 38(5): 1495 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsimikas, E. S. Brilakis, R. J. Lennon, E. R. Miller, J. L. Witztum, J. P. McConnell, K. S. Kornman, and P. B. Berger Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events J. Lipid Res., February 1, 2007; 48(2): 425 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M McMahon, J Grossman, W Chen, and B H Hahn Inflammation and the pathogenesis of atherosclerosis in systemic lupus erythematosus Lupus, November 1, 2006; 15(11_suppl): 59 - 69. [Abstract] [PDF]
|
|
|
|
 |
|
 S. G. Tsouli, D. N. Kiortsis, V. Xydis, M. I. Argyropoulou, M. Elisaf, and A. D. Tselepis Antibodies Against Various Forms of Mildly Oxidized Low-Density Lipoprotein Are Not Associated With Carotid Intima-Media Thickness in Patients With Primary Hyperlipidemia Angiology, October 1, 2006; 57(5): 615 - 622. [Abstract] [PDF]
|
|
|
|
|
|
S. G. Tsouli, D. N. Kiortsis, E. S. Lourida, V. Xydis, L. D. Tsironis, M. I. Argyropoulou, M. Elisaf, and A. D. Tselepis Autoantibody titers against OxLDL are correlated with Achilles tendon thickness in patients with familial hypercholesterolemia J. Lipid Res., October 1, 2006; 47(10): 2208 - 2214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mayr, S. Kiechl, S. Tsimikas, E. Miller, J. Sheldon, J. Willeit, J. L. Witztum, and Q. Xu Oxidized Low-Density Lipoprotein Autoantibodies, Chronic Infections, and Carotid Atherosclerosis in a Population-Based Study J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2436 - 2443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, S. Kiechl, J. Willeit, M. Mayr, E. R. Miller, F. Kronenberg, Q. Xu, C. Bergmark, S. Weger, F. Oberhollenzer, et al. Oxidized Phospholipids Predict the Presence and Progression of Carotid and Femoral Atherosclerosis and Symptomatic Cardiovascular Disease: Five-Year Prospective Results From the Bruneck Study J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2219 - 2228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Quyyumi Women and Ischemic Heart Disease: Pathophysiologic Implications From the Women's Ischemia Syndrome Evaluation (WISE) Study and Future Research Steps J. Am. Coll. Cardiol., February 7, 2006; 47(3_Suppl_S): S66 - S71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Binder, P. X. Shaw, M.-K. Chang, A. Boullier, K. Hartvigsen, S. Horkko, Y. I. Miller, D. A. Woelkers, M. Corr, and J. L. Witztum Thematic review series: The Immune System and Atherogenesis. The role of natural antibodies in atherogenesis J. Lipid Res., July 1, 2005; 46(7): 1353 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schneider, B. Verges, A. Klein, E. R. Miller, V. Deckert, C. Desrumaux, D. Masson, P. Gambert, J.-M. Brun, J. Fruchart-Najib, et al. Alterations in Plasma Vitamin E Distribution in Type 2 Diabetic Patients With Elevated Plasma Phospholipid Transfer Protein Activity Diabetes, October 1, 2004; 53(10): 2633 - 2639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsimikas, J. L. Witztum, E. R. Miller, W. J. Sasiela, M. Szarek, A. G. Olsson, G. G. Schwartz, and for the Myocardial Ischemia Reduction with Aggress High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial Circulation, September 14, 2004; 110(11): 1406 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Karvonen, M. Paivansalo, Y. A. Kesaniemi, and S. Horkko Immunoglobulin M Type of Autoantibodies to Oxidized Low-Density Lipoprotein Has an Inverse Relation to Carotid Artery Atherosclerosis Circulation, October 28, 2003; 108(17): 2107 - 2112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Virella and M. F. Lopes-Virella Lipoprotein Autoantibodies: Measurement and Significance Clin. Vaccine Immunol., July 1, 2003; 10(4): 499 - 505. [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, C. Bergmark, R. W. Beyer, R. Patel, J. Pattison, E. Miller, J. Juliano, and J. L. Witztum Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes J. Am. Coll. Cardiol., February 5, 2003; 41(3): 360 - 370. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||