© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Systemic Inflammatory Parameters in Patients With Atherosclerosis of the Coronary and Peripheral Arteries
From the Institut für Klinische Chemie und Laboratoriumsmedizin (M.E., R.J., M.F., G.A., P.C.), the Institut für Arterioskleroseforschung (M.E., H.R., R.J., M.F., H.S., G.B., G.A., P.C.), and the Medizinische Klinik und Poliklinik (H.R., S.K., G.B.), Innere Medizin C, Westfälische Wilhelms-Universität, Münster; and the Abteilung für Klinische Chemie und Zentrallaboratorium (J.O.S., J.K.), Philipps-Universität, Marburg, Germany.
Correspondence to Dr Paul Cullen, Institut für Arterioskleroseforschung, Domagkstrasse 3, D-48149 Muenster, Germany. E-mail cullen{at}uni-muenster.de
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Abstract—Plasma concentration of markers of inflammation are increased in patients with atherosclerosis. However, it is unclear whether the pattern and magnitude of this increase vary with the site and extent of disease. In 147 patients undergoing semiquantitative coronary angiography, we measured the acute-phase reactants C-reactive protein (CRP) or serum amyloid A (SAA); the proinflammatory cytokine interleukin 6 (IL-6); the active and total fractions of the anti-inflammatory cytokine transforming growth factor-ß (TGF-ß); the macrophage activation marker neopterin; and the infection marker procalcitonin. Compared with 62 patients without either coronary artery disease (CAD) or peripheral artery disease (PAD), 57 patients with CAD but no PAD showed greater median CRP (0.4 versus 0.2 mg/dL, P=0.004) and IL-6 (3.8 versus 1.6 pg/mL, P=0.007) levels and a lower level of active-TGF-ß (57 versus 100 ng/mL, P=0.038). Moreover, CRP, IL-6, and neopterin levels showed a positive and the active TGF-ß level a negative correlation with the extent of coronary atherosclerosis. Compared with these 57 patients with CAD alone, 15 patients with PAD and CAD had higher median levels of SAA (17 versus 7 mg/mL, P=0.008), IL-6 (12 versus 4 pg/mL, P=0.002), neopterin (14 versus 11 mg/dL, P=0.006), and total TGF-ß (11834 versus 6417 ng/L, P=0.001). However, these strong univariate associations of markers of inflammation and atherosclerosis were lost in multivariate analysis once age, sex, and high density lipoprotein cholesterol or fibrinogen were taken into account. Increased plasma levels of CRP, SAA, IL-6, TGF-ß, neopterin, and procalcitonin constitute an inflammatory signature of advanced atherosclerosis and are correlated with the extent of disease but do not provide discriminatory diagnostic power over and above established risk factors.
Key Words: atherosclerosis • coronary artery disease • peripheral artery disease • markers of inflammation • acute-phase response
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For some time, evidence has been accumulating that inflammation plays an important role in both the initiation and progression of atherosclerosis of the coronary, carotid, and peripheral arteries.1 2 3 For example, levels of C-reactive protein (CRP), an acute-phase reactant, >0.3 mg/dL but still within the reference range, have been found to predict unstable angina pectoris, myocardial infarction, and sudden cardiac death.4 In addition, 2 recent reports from the Physicians' Health Study indicate that in apparently healthy men, even slight increases in CRP below this cut-point increase the risk for future myocardial infarction, stroke, and peripheral artery disease (PAD).5 6 Serum amyloid A (SAA), an apolipoprotein predominantly bound to HDL, is an acute-phase reactant that indicates systemic inflammatory activity with at least the sensitivity of CRP.7 SAA levels were also reported to be increased in coronary atherosclerosis.8 A third acute-phase reactant of interest is fibrinogen.9 10 Numerous workers have reported an increase in fibrinogen in atherosclerosis,11 12 but it is unclear whether this elevation is mainly a cause or a result of the disease, although both may be true. The acute-phase response is under tight control of interleukin 6 (IL-6),13 which is produced to a large extent by macrophages.14 Expression of IL-6 has been demonstrated in atherosclerotic plaques,14 15 16 17 but little information exists on circulating levels of IL-6 in patients with atherosclerosis of the coronary or peripheral arteries.
In recent years, numerous experimental studies have demonstrated an important pathophysiological role of the cytokine transforming growth factor-ß (TGF-ß) in the pathogenesis of atherogenesis.18 19 20 21 Clinical studies have concentrated on both the active and total fractions of this cytokine. One study found that serum levels of active TGF-ß were much lower in patients with atherosclerosis of all 3 coronary arteries than in persons without coronary atherosclerosis, with no overlap between these groups.22 In another study, increased plasma concentrations of active TGF-ß were associated with the presence of coronary artery disease (CAD).23
The role of latent bacterial and viral infections in the pathogenesis of atherosclerosis has been the subject of much recent debate.24 Neopterin, a specific marker of macrophage activation,25 is commonly used to screen for subclinical viral infections26 and has been found to be elevated in the circulation of patients with atherosclerosis of the carotid,27 coronary,28 and peripheral29 arteries. Another newer marker of infection is the peptide hormone procalcitonin (PCT). An elevated level of PCT is thought to indicate systemic exposure of the body to bacterial endotoxins and/or exotoxins.30 At present, it is unknown whether microbially induced atherosclerosis is associated with elevated levels of PCT.
Despite the studies performed to date, it is not known whether the pattern of inflammation parameters differs between atherosclerosis of the coronary and peripheral arteries. In addition, the mechanisms relating the increased levels of markers of inflammation to atherosclerosis are, in general, unknown. We therefore undertook the present study in 147 consecutive patients undergoing semiquantitative coronary angiography to address the following questions: (1) Is there a consistent pattern of markers of inflammation in human atherosclerosis? (2) If so, does the pattern of markers in CAD differ from that in PAD? (3) Are the plasma concentrations of markers of inflammation correlated with the extent of atherosclerotic disease? (4) To what extent are markers of inflammation correlated with each other and/or with metabolic risk markers of atherosclerosis?
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Patients
All patients admitted to our university hospital for elective coronary angiography in the months of May and June 1997 were screened for inclusion in the study. Patients were excluded if they were critically ill or hemodynamically unstable, if they had undergone surgery or suffered a myocardial infarction within the previous 3 months, if they were receiving drugs (except heparin) parenterally, or if they had a stenosis of
50% of the left main stem coronary artery. Unstable angina
pectoris was defined as pain at rest with at least 2 episodes during
the previous 48 hours, at least 1 of which lasted >20 minutes, or
ST-segment deviations that were diagnostic of myocardial
ischemia during anginal attacks, with no elevation of the MB
fraction of creatine kinase or lactate dehydrogenase on admission to
hospital. Current medications, cardiovascular risk
factors, and concomitant illnesses were recorded. A history was
taken and physical examination performed in each patient by the same
investigator (H.R.). Because this study required angiographic
assessment of the coronary arteries, no true control group was
established because of the unacceptable health risk of coronary
angiography in persons in whom this investigation is not medically
warranted. All patients were informed of the aim of the study and gave
their consent for blood sample acquisition. The study was approved by
the hospital Ethics Committee.
The clinical characteristics of the patients in this study are given in
Table 1
. The frequencies of hypertension,
smoking, and diabetes mellitus and the mean body mass index were in
agreement with reported data for the general German population of this
age. Of the 147 patients (107 men and 40 women) who underwent
coronary angiography, 78 (53%) had coronary
atherosclerosis as defined by the presence of 1
stenosis of 70% in 1 of the major coronary branches.
Ninety-three patients (63%) had a history of angina pectoris. One-,
2-, and 3-vessel disease was present at about the same frequency.
Owing to exclusion of hemodynamically unstable or
critically ill patients, only 7 participants (5%) had symptoms of
unstable angina pectoris. Twenty-eight patients (19%) had symptoms
and/or clinical signs of PAD. In 17 of these 28 patients (11 men, 6
women), atherosclerosis of the lower-limb arteries was
confirmed angiographically. Twenty patients had carotid bruits or a
history of intermittent claudication, of whom 12 had evidence of
carotid atherosclerosis on B-mode ultrasound
examination. All 12 patients with sonographically proven carotid
stenosis also had angiographic evidence of lower-limb
atherosclerosis. Eleven patients with unconfirmed PAD
were excluded from the analysis. Of the remaining 136 patients, 62 were
angiographically free of atherosclerotic disease, 57 had CAD alone, 2
had PAD alone, and 15 patients had both CAD and PAD (Table 2). A third of all patients were
receiving statins for treatment of
hypercholesterolemia, half were receiving
acetylsalicylic acid, and 7% were on
phenprocoumon.
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Coronary Angiography
In the 93 patients with angina pectoris, coronary
angiography was performed to define the extent of CAD; in the remaining
54 patients, the investigation was performed as part of a work-up of
cardiac arrhythmia. Angiography was performed predominantly by
the technique of Judkins and, rarely, the technique of Sones. A Judkins
catheter was introduced via the femoral artery, and Ultravist 370
(Schering AG) was injected selectively in the left ventricle and the
coronary arteries, which were visualized in multiple standard
pro-jections by using a biplane angiographic system (Philips) and
recorded on CD-ROM using the DICOM standard.
Angiographic Scores
The grade and type of coronary
atherosclerosis were scored from the angiographic data
retrieved in digital format from CD-ROM by counting the number of
affected vessels and by calculating a stenosis
score31 32 as follows. The coronary artery system
as displayed in the angiographic movie was first divided into 8
segments: left main stem, left anterior descending artery, diagonal
branch, first septal perforator, left circumflex artery, marginal or
posterolateral branch, right coronary artery, and main
posterior descending branch. The most severe stenosis in each
of these segments was then scored, with 0 points for no
stenosis, 1 point for 1% to 49% reduction in vessel diameter,
2 points for 50% to 74% reduction, 3 points for 75% to 99%
reduction, and 4 points for total occlusion of the segment. Scores for
each segment were added and therefore the total score could range from
0 to 32 points.31
Assessment of PAD
PAD was suspected if the patient reported intermittent
claudication, if pedal or popliteal pulses were undetectable, or if
arterial bruits were heard over the iliac or popliteal
arteries. Most of these patients were examined angiographically;
definite PAD was defined as the presence of 1 stenosis of
50% in the iliac, femoral, popliteal, or crural
arteries.33 Patients with suspected PAD in whom
angiography could not be performed for technical reasons or in whom
angiography was inconclusive were classified as "unconfirmed PAD."
All other patients were classified as having no PAD.
Blood Sampling
Between 8 and 10 AM of the day of coronary
angiography but before it was performed and after an overnight fast,
blood was drawn by venipuncture without use of a tourniquet
with a 21-gauge needle directly into chilled 10-mL plain tubes and into
10-mL tubes containing EDTA (final concentration 0.1%) or 3.13%
trisodium citrate (1/10 of volume). Samples were immediately
placed on ice and transported to the laboratory. Within 30 minutes
after venipuncture, platelet-poor plasma was isolated
by centrifugation at 1200g for 30 minutes at
4°C and immediately stored in aliquots of 1 mL at -86°C. After
being allowed to clot for 2 hours at room temperature, serum was
isolated by centrifugation at 800g for 20
minutes at room temperature and stored in aliquots of 1 mL at -86°C
until analysis. Storage time of samples ranged from 2 to 4
months. Measurements of all parameters were performed in a
single batch at the end of the collection period from material that was
thawed only once.
Immunologic and Clotting Parameters
CRP was measured by means of a particle-enhanced
immunonephelometric assay with a lower detection limit of 0.0175 mg/dL
(manufacturer's data; N Latex CRP mono, Dade Behring
Diagnostics) on a nephelometric analyzer (BN II,
Dade Behring Diagnostics). SAA was measured by solid-phase
sandwich ELISA (Cytoscreen, BioSource). IL-6 was also measured by
solid-phase sandwich ELISA (IL6-ELISA-CB, BioSource) on a Cobas Core II
analyzer (Roche Diagnostics). Active and total
TGF-ß were measured both in platelet-poor plasma (2000 to 5000
platelets/µL) and in serum. No correlation was found between the
TGF-ß concentration in plasma and the platelet count. Total
TGF-ß was measured using a sandwich ELISA assay developed at the
University of Marburg, Germany34 ; active TGF-ß was
measured using a commercial test kit (Biotrak, Amersham) according to
the manufacturer's instructions. An automated pipetting robot (Tecan
Genesis RSP 150) was used for all pipetting steps, and an automated
washer was used for washing between incubation. Neopterin was measured
by competitive enzyme immunoassay (Elitest, Brahms). PCT was measured
using an immunoluminometric assay (Lumitest PCT, Brahms) on a Stratec
SL300 autoanalyzer (Stratec Elektronic). Clottable fibrinogen
was determined according to the method of Clauss35 on a
Behring BCS coagulation analyzer using Multifibren U (Dade
Behring Diagnostics). Plasminogen
activator inhibitor 1 (PAI-1) activity was
measured with the Chromolize PAI-1 assay kit from Biopool.
Other Laboratory Parameters
Total serum cholesterol and
triglycerides were measured using enzymatic
assays.36 HDL cholesterol (HDL-C) was
determined by a precipitation method (based on Reference 3737 ;
Boehringer Mannheim) on a Hitachi 917 autoanalyzer.
LDL-C was calculated using the Friedewald formula. Lp(a) was measured
by nephelometry using a latex-enhanced immunoassay (Immuno) on a
Hitachi 917 autoanalyzer. Serum glucose was measured using the
glucose oxidase method38 and uric acid by the UA Plus
method.39 Homocysteine was measured by reverse-phase
high-performance liquid chromatography with a
commercial assay kit (Chromsystems) on an isocratic liquid
chromatograph (Kontron) interfaced with a fluorescence
detector (model RF-535, Shimadzu).
Statistics
Because many variables were not normally distributed,
nonparametric statistical tests were used throughout.
Groups were compared using a 2-tailed Mann-Whitney U test. The
correlations between inflammatory markers or metabolic
parameters and the coronary stenosis score
were calculated using Spearman rank correlations. Probabilities <0.05
were regarded as significant. In preliminary analyses, several
immunologic and metabolic parameters were shown
to vary with sex, smoking status, and age. The numbers of women and
smokers in this study, however, were too small to allow meaningful
examination of these subgroups separately (Table 1
). To avoid
confounding, appropriate corrections were therefore made whenever the
sex distribution and number of smokers varied significantly between the
subgroups. No age correction was performed because of the similar age
distribution in all subgroups. These corrections are likely to have
increased the chance of overlooking true associations, rather than
increasing the chances of identifying associations where none were
present. Thus, it is unlikely that our findings are the result of
bias or chance. To avoid misclassification, the 11 patients with
unconfirmed PAD were excluded from analysis. The group of 2
patients with PAD but without CAD was also excluded because of its
small size. Thus, 134 patients were available for statistical
analysis. For analysis of parameters in
CAD, the 57 patients with CAD but without PAD ("CAD, no PAD") were
compared with the 62 patients without either CAD or PAD ("no CAD, no
PAD"; Table 3). For analysis of
parameters in PAD, the 15 patients with CAD and PAD
("CAD, PAD") were compared with the 57 patients with CAD but
without PAD ("CAD, no PAD"). Finally, for completeness, the "CAD,
PAD" group was compared with the "no CAD, no PAD" group. Because
significant correlations between the various inflammatory and
metabolic parameters were found in this and
other studies, we performed logistic regression analysis of all
parameters that were found in univariate
analysis to differ significantly between CAD patients and
controls. Too few patients had PAD to allow meaningful logistic
regression analysis for this subgroup. All statistical
calculations were performed using the Statistical Package for the
Social Sciences (SPSS version 8.0) computer
program.
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Metabolic and Immunologic Markers in CAD
Compared with patients without CAD, patients with CAD demonstrated significantly raised levels of CRP, fibrinogen, and IL-6 (Table 3
). The median level of active TGF-ß, by contrast, was
significantly lower in the group with CAD. The other immunologic
parameters did not differ between the groups. Among the
metabolic risk markers, HDL-C level was significantly lower
while fasting glucose level was higher in patients with CAD than in
patients without CAD.
Metabolic and Immunologic Parameters
in PAD
There was greater evidence of immunologic activation in patients
with PAD and CAD than in patients with CAD alone (Table 3). SAA,
fibrinogen, IL-6, total TGF-ß, neopterin, and PCT were all higher in
patients with PAD. The level of CRP, though not increased in patients
with CAD and PAD compared with those with CAD alone, was significantly
greater than in patients without either CAD or PAD
(P<0.001). Of the metabolic risk factors, only
triglycerides and uric acid were increased in patients with
CAD and PAD compared with patients with CAD alone.
Comparison of Patients With CAD and PAD With Patients Without
Atherosclerosis
With the exception of active TGF-ß, all parameters
of inflammation that were significantly different between patients with
and without CAD also differed significantly between patients with CAD
and PAD compared with patients without atherosclerosis.
Although total TGF-ß was significantly greater in patients with CAD
and PAD compared with those with CAD alone, the difference between
patients with PAD and CAD and those without
atherosclerosis was not significant.
Triglyceride and uric acid were significantly greater and
HDL-C significantly lower in patients with CAD and PAD than in those
without atherosclerosis.
Correlation of Metabolic and Immunologic
Parameters With Coronary Stenosis Score
Levels of CRP, fibrinogen, and IL-6 showed a significant positive
correlation and active TGF-ß a significant negative correlation with
the extent of coronary stenosis (Table 4). Among the metabolic risk
factors, HDL-C showed a negative correlation and glucose a positive
correlation with the extent of coronary
atherosclerosis as measured by the coronary
stenosis score.
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Correlation Between Immunologic and Metabolic
Laboratory Parameters
To explore the relationships among the markers of inflammation,
among the atherosclerosis-associated
metabolic markers, and between these 2 sets of
parameters, nonparametric correlations were
calculated between and among these groups (Table 5). As expected, many correlations were
found among the atherosclerosis-associated
metabolic factors. However, a large number of correlations
also existed between metabolic and immunologic markers. In
particular, neopterin, a specific marker of monocyte-macrophage
activation,25 was closely correlated with homocysteine
(0.68, P<0.01) and uric acid (0.32, P<0.01)
levels. Also of note was the close correlation between fibrinogen, a
sensitive marker of the acute-phase response, and not only CRP (0.57,
P<0.001), SAA (0.50, P<0.001), and IL-6 (0.50,
P<0.001) but also neopterin (0.36, P<0.01) and
PCT (0.34, P<0.01). By contrast, of the
metabolic parameters, only HDL-C showed a
negative correlation with fibrinogen (-0.25, P<0.01).
Several close correlations also existed among other immunologic
markers, the closest being between the proinflammatory cytokine
IL-6 and the acute phase reactants CRP (0.64, P<0.001) and
SAA (0.47, P<0.001), followed by IL-6 and the marker of
macrophage activation, neopterin (0.44, P<0.001) as
well as between IL-6 and the marker of infection, PCT (0.40,
P<0.01). Correlations of lower significance also existed
between neopterin and SAA as well as active TGF-ß and between PCT and
CRP as well as SAA. The number and strength of correlations among the
immunologic markers were in general similar to those among the
atherosclerosis-associated metabolic
parameters.
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Logistic Regression Analysis
In logistic regression analyses taking account of age and
sex, levels of HDL-C, fibrinogen, and triglycerides were
significantly associated with the presence of CAD. Taking age, sex, and
triglycerides into account, of the immunologic
parameters only CRP was found to be significantly
associated with the presence of CAD. However, CRP was no longer
significantly associated with CAD when fibrinogen or HDL-C was added to
age, sex, and triglycerides in the logistic regression
analysis. Thus, in the presence of fibrinogen or HDL-C, markers
of inflammation or of the acute-phase response did not additionally
discriminate between patients with and without CAD.
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The main result of this study was the finding of increased levels of parameters of inflammation in CAD and PAD, whereby more parameters were elevated and the elevation was more clear-cut in patients with both CAD and PAD compared with patients with CAD alone. This result would seem to indicate that the levels of immunologic markers may indicate the extent of atherosclerotic disease, a conclusion that is supported by the positive correlation between CRP, fibrinogen, and IL-6 and the negative correlation between active TGF-ß and the extent of coronary sclerosis. It is of note that these elevations of immunologic parameters occurred despite the near absence of significant differences in the levels of atherosclerosis-associated metabolic parameters between patients with and those without atherosclerosis. Previous workers have shown an increase in the level of circulating immunologic parameters in atherosclerosis in both cross-sectional22 23 27 and prospective 4 6 10 29 33 40 studies. Our study extends these results to show that a core inflammatory signature can be identified in the blood of patients with atherosclerotic disease.
The stenosis score used in our analysis is a measure of both the severity of CAD—as it grades the most critical stenosis in 1 of 8 coronary segments—and of the extent of coronary atherosclerosis.31 32 In our patients, inflammatory markers were clearly increased in atherosclerotic disease of the coronary and peripheral arteries, even in the absence of unstable angina pectoris (present in only 5% of patients) or myocardial infarction. In previous cross-sectional studies,4 41 an elevated level of CRP was found to be indicative of "active" CAD manifesting as unstable angina pectoris, plaque rupture, or acute myocardial infarction, whereas in prospective studies, even slight differences in the median CRP levels were found to be predictive of myocardial infarction, stroke, and PAD in men.6 In the present report, CRP levels were slightly higher than those reported in these studies. This may reflect differences in the methods used and may also be due to differences in patient selection. CRP levels in our patients with CAD were significantly higher than in those without CAD. Levels of CRP in patients with CAD and PAD did not differ significantly from those in patients with CAD alone but were greater than those in patients without atherosclerosis. This lack of a further significant increase of CRP in PAD plus CAD compared with CAD alone may reflect the play of chance, in view of the small number of patients with PAD analyzed. Median levels of SAA, an acute-phase protein that behaves in a very similar fashion to CRP, were significantly elevated in PAD. Thus, our data indicate that significant elevations of CRP may be present in stable coronary atherosclerosis in the absence of "activation." Moreover, in contrast to a report by Liuzzo and colleagues4 but in agreement with a previous report from our group,12 the level of CRP was positively correlated with both the grade and extent of coronary disease, indicating that this parameter is not only a marker of disease presence but also a quantitative indicator of disease extent.
In our patients, fibrinogen was also elevated in both CAD and PAD and was significantly correlated with the extent of CAD, indicating that it—like CRP—is a marker not only of the presence of atherosclerosis, as has previously been shown,10 11 40 42 43 but also of the extent of disease. A similar result has been previously reported by Heinrich and colleagues from our group.12
What is the cause of this increase in acute-phase reactants in atherosclerosis? During immunologic reactions, CRP, SAA, and fibrinogen synthesis in the liver increase in response to stimulation by proinflammatory cytokines. In our patients, IL-6 was elevated in both CAD and PAD, and the level of IL-6 was correlated with the extent of CAD. A main source of IL-6 is activated macrophages,14 and IL-6 has been shown to strongly influence levels of CRP,13 SAA,44 and fibrinogen in vivo.45 46 Moreover, IL-6 is present within the arterial wall.14 15 16 17 In the participants in our study, the level of neopterin, a specific marker of activated macrophages,25 was higher in patients with PAD than in patients without PAD. This increase in neopterin levels may be an indicator of macrophage activation. Several studies have confirmed that activated macrophages are present within the atherosclerotic plaque.2 46 47 48 Taken together with our results, these findings suggest that the source of the proinflammatory cytokines in atherosclerosis may, at least partially, be the macrophages within the arterial wall.
It is also possible that at least some of the increased CRP levels in our patients with atherosclerosis may have been synthesized by activated macrophages within the arterial wall.49 50 51 Such activation of plaque macrophages may reflect chronic infection of the arterial wall,24 52 53 54 55 56 57 58 59 or it may be the result of their interaction with oxidized or otherwise-modified lipoproteins.60 61
To further explore markers of infection in atherosclerosis, we also measured the level of PCT, which was increased in patients with PAD. PCT is thought to derive mainly from cells of neuroendocrine origin throughout the body and is produced almost exclusively as part of a systemic response to bacterial endotoxins or exotoxins.30 In sepsis, however, the level of PCT is generally 1 to 3 orders of magnitude greater than that seen in our patients. Thus, the pathophysiological significance of the slight increase in PCT seen in our patients with PAD is uncertain but may reflect a low-grade inflammatory response, perhaps in response to primary or secondary bacterial infection.57
It is also possible that the increase in markers of inflammation in atherosclerosis is not a response to infection or modified lipoproteins within the arterial wall but reflects a low-grade primary activation of the immune system.62 For example, studies by Wick and others have found evidence of inflammatory activity with cellular infiltrates in the arteries of children and young adults before the development of atherosclerosis.63 64 65 Conversely, the increased level of parameters of inflammation may contribute directly to atherogenesis. CRP has been shown to increase the opsonization and uptake of lipid complexes by macrophages,66 and SAA modifies HDL particles such that their affinity for monocytes/macrophages is increased.67 Moreover, inflammatory parameters directly influence metabolic parameters; IL-6, for example, sharply lowers HDL-C and alters lipoprotein composition.68
In our patients, active TGF-ß was reduced in coronary atherosclerosis, while total TGF-ß was increased in PAD. Moreover, the levels of active TGF-ß were inversely correlated with the extent of coronary atherosclerosis. This finding of a decrease in active TGF-ß in patients with CAD is in agreement with the report of Grainger et al,22 even though the association in our patients was less marked and these levels showed some degree of overlap in patients with 3-vessel disease and those with normal coronary arteries. Results from different studies on TGF-ß in atherosclerosis are inconsistent. This may be due to differences in preanalytic design, including measurement in different matrixes (serum22 versus plasma23 ) and the use of different methods for measurement of TGF-ß. The phylogenetically highly conserved TGF-ß possesses low immunogenicity. Available antibodies therefore have low specificity and affinity and detect different epitopes. To circumvent theses problems, some groups have used recombinant truncated forms of the TGF-ß receptor as capture ligand.69 However, the lack of international reference material prevents efforts to standardize these tests. To address these issues, we measured active TGF-ß in plasma and serum in all our patients by using a number of different antibody-based assay systems (Amersham, BioSource, Promega, Genzym, and the Marburg-assay) and a TGF-ß receptor–based system (R&D Inc; data not shown). The results of these measurements showed a low correlation between the tests as well as differences in concentrations of active TGF-ß of 1 to 2 orders of magnitude. The best correlation of active TGF-ß with CAD was found with the Amersham assay (r=-0.24, P<0.05). The details of TGF-ß measurements in our patients will be presented in detail elsewhere.
Multiple highly significant correlations were seen in the present study between the levels of CRP, SAA, IL-6, neopterin, PCT, and fibrinogen. Correlations with PAI-1 and TGF-ß were less marked. This may indicate that the former 6 parameters form a core inflammatory response in atherosclerosis, which may be driven by activation of macrophages within the arterial wall. It is notable that the level of neopterin, a specific marker of macrophage activation,25 was closely correlated not only with immunologic parameters (including fibrinogen) but also with the metabolic parameters urate, triglycerides, and homocysteine and inversely with HDL-C. Correlation coefficients can provide no information on cause and effect. However, these correlations are consistent with the hypothesis that at least part of these metabolic changes may be secondary to activation of inflammation.
Compared with the clearly increased levels of many inflammatory parameters in atherosclerosis in the present study, differences in the metabolic parameters between patients with and without CAD or PAD were fewer and of lesser extent, although HDL-C was negatively correlated and glucose was positively correlated with the extent of coronary atherosclerosis. The relative lack of differences in metabolic parameters between patients with and without atherosclerosis may have been partly a result of drug therapy or of modifications of life style or dietary habits undertaken by the patients in response to the diagnosis of atherosclerosis. Nevertheless, even with the relatively small number of patients in this present study, marked changes in immunologic parameters were seen, which may indicate that these markers are superior indicators of existent disease in the individual patient.
Despite the differences seen in univariate analysis, multivariate logistic regression analysis revealed that only CRP provided additional discriminatory power in the identification of CAD, once age and sex were taken into account. However, when fibrinogen, a positive acute-phase reactant, or HDL-C, a negative acute-phase reactant, was taken into account, none of the parameters of inflammation analyzed in the present study provided additional information. It would therefore appear that determination of parameters of inflammation does not provide information over and above that provided by fibrinogen or HDL-C. Many of the studies that have shown an increase in immunologic parameters in atherosclerosis either did not adjust for age (eg, recent analyses of CRP levels in the Physicians' Health Study by Ridker and colleagues5 6 ) or failed to perform multivariate regression analysis (eg, studies of TGF-ß in CAD by Grainger et al22 ). In studies in which such analyses were performed, differences between patients with and without atherosclerosis were much attenuated when age was included in the regression equation.27 It is of note that on multivariate analysis, the most effective discrimination between patients with and without CAD was achieved with the well-known "classic" risk factors determined in such prospective studies as the Framingham Heart Study70 or the Münster Heart Study,71 despite the sometimes striking differences in the levels of parameters of inflammation seen on univariate analysis. The discriminatory power of the markers of inflammation in the present study was explained to a great degree by fibrinogen and HDL-C. This may reflects the fact that HDL-C and fibrinogen are not only indicators of atherosclerotic risk in their own right, as components of lipid metabolism or the clotting system, but also positive and negative acute-phase reactants, respectively.
In summary, the present study suggests that increased circulating levels of CRP, SAA, IL-6, neopterin, PCT, and fibrinogen represent a core inflammatory signature of advanced atherosclerotic disease and that the level of these markers may reflect the whole-body burden of atherosclerotic tissue. However, on multivariate logistic regression analysis, the discriminatory power of these markers of inflammation was explained by fibrinogen or HDL-C. Thus, performance of these expensive and technically demanding assays cannot, at present, be recommended for the assessment of atherosclerotic disease in clinical practice.
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Acknowledgments |
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The authors gratefully acknowledge the excellent technical assistance of Renate Kwiotek, Ulrike Ehmann, and Kathrin Grussel, Institute of Clinical Chemistry and Laboratory Medicine, University of Münster, Münster, Germany.
Received January 4, 1999; accepted February 11, 1999.
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J.-J. Li, H. Jiang, C.-X. Huang, C.-H. Fang, Q.-Z. Tang, H. Xia, J. Liu, and G.-S. Li Elevated Level of Plasma C-reactive Protein in Patients with Unstable Angina: Its Relations with Coronary Stenosis and Lipid Profile Angiology, May 1, 2002; 53(3): 265 - 272. [Abstract] [PDF]
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 M. Visser, M. Pahor, D. R. Taaffe, B. H. Goodpaster, E. M. Simonsick, A. B. Newman, M. Nevitt, and T. B. Harris Relationship of Interleukin-6 and Tumor Necrosis Factor-{alpha} With Muscle Mass and Muscle Strength in Elderly Men and Women: The Health ABC Study J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2002; 57(5): M326 - 332. [Abstract] [Full Text]
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I. M. van der Meer, M. P.M. de Maat, M. L. Bots, M. M.B. Breteler, J. Meijer, A. J. Kiliaan, A. Hofman, and J. C.M. Witteman Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis: The Rotterdam Study Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 838 - 842. [Abstract] [Full Text] [PDF]
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D.J. Brull, H.E. Montgomery, J. Sanders, S. Dhamrait, L. Luong, A. Rumley, G.D.O. Lowe, and S.E. Humphries Interleukin-6 Gene -174G>C and -572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1458 - 1463. [Abstract] [Full Text] [PDF]
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C. G. Panousis, G. Evans, and S. H. Zuckerman TGF-{beta} increases cholesterol efflux and ABC-1 expression in macrophage-derived foam cells: opposing the effects of IFN-{{gamma}} J. Lipid Res., May 1, 2001; 42(5): 856 - 863. [Abstract] [Full Text]
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M. Langlois, D. Duprez, J. Delanghe, M. De Buyzere, and D. L. Clement Serum Vitamin C Concentration Is Low in Peripheral Arterial Disease and Is Associated With Inflammation and Severity of Atherosclerosis Circulation, April 10, 2001; 103(14): 1863 - 1868. [Abstract] [Full Text] [PDF]
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A. von Eckardstein, J.-R. Nofer, and G. Assmann High Density Lipoproteins and Arteriosclerosis : Role of Cholesterol Efflux and Reverse Cholesterol Transport Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 13 - 27. [Abstract] [Full Text] [PDF]
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T. Ito, U. Ikeda, M. Shimpo, K. Yamamoto, and K. Shimada Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells Circulation, November 14, 2000; 102(20): 2522 - 2527. [Abstract] [Full Text] [PDF]
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 C. M. Bloor Depression: A Symptom of Coronary Artery Disease or a Pathogenetic Factor? Psychosom Med, September 1, 2000; 62(5): 606 - 607. [Full Text] [PDF]
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 Z. Mallat, A. Gojova, C. Marchiol-Fournigault, B. Esposito, C. Kamate, R. Merval, D. Fradelizi, and A. Tedgui Inhibition of Transforming Growth Factor-{beta} Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice Circ. Res., November 9, 2001; 89(10): 930 - 934. [Abstract] [Full Text] [PDF]
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