© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Plasma Concentrations of Interleukin-6 and Abdominal Aortic Diameter Among Subjects Without Aortic Dilatation
From the Cardiovascular Division, Brigham and Women's Hospital, and the Department of Laboratory Medicine, Children's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Richard T. Lee, MD, Cardiovascular Division, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail rtlee{at}bics.bwh.harvard.edu
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Abstract |
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Abstract—Previous studies suggest that cytokine-induced tissue inflammation may participate in the pathogenesis of abdominal aortic aneurysms. Serum inflammatory markers may reflect arterial inflammation in asymptomatic phases of the aneurysmal disease. We studied 120 outpatients (62 men; age, 65±9 years) by ultrasound evaluation of the abdominal aorta to evaluate the association of circulating levels of interleukin-6 (IL-6) with abdominal aortic diameter in subjects with normal aortic size. Aortic diameter was measured at the infrarenal level and indexed for body surface area. Seven patients with abdominal aortic dilatation (indexed aortic diameter, >1.3 cm/m2) were also identified. Plasma concentrations of IL-6, serum amyloid A (SAA), C-reactive protein (CRP), total homocysteine, and lipids were measured. Among the 113 subjects without aortic dilatation, indexed aortic diameter was positively associated with serum levels of IL-6 (P<0.01), SAA (P<0.01), and total homocysteine (P=0.01). IL-6 levels increased in a stepwise fashion among dichotomized groups of aortic size (low and high aortic diameters) and peaked in patients with aortic dilatation (2.3±1.2 versus 2.7±0.9 versus 3.2±0.9 pg/mL, respectively; P for trend=0.039). None of the serum lipid measurements correlated with abdominal aortic diameter. Although CRP levels were associated with SAA levels (r=0.60; P<0.001), associations between CRP and aortic diameter were nonsignificant. In multivariate analysis, levels of IL-6 (P=0.02), SAA (P=0.001), and total homocysteine (P<0.001) were independent correlates of indexed aortic diameter. In conclusion, circulating levels of IL-6, SAA, and total homocysteine may reflect processes involved in the early phases of abdominal aortic aneurysm formation, before dilation of the abdominal aorta is established. These data support a role for chronic inflammation in the progression of asymptomatic aortic disease.
Key Words: atherosclerosis • inflammation • aortic aneurysm • homocysteine
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Introduction |
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Increasing evidence suggests that elevated levels of acute-phase proteins and their determinants occur in acute coronary syndromes,1 2 and may also predict future cardiovascular events.3 4 5 6 Interleukin-6 (IL-6) is an inflammatory cytokine that seems to play a pivotal role in the acute-phase response and elevated levels of IL-6 have been associated with worse prognosis in unstable angina.7 In addition, circulating levels of IL-6 are elevated in patients with abdominal aortic aneurysms (AAAs), compared with controls and patients with coronary heart disease.8 These findings support several observations that indicate that tissue inflammation, possibly mediated by IL-6, participates in the pathogenesis of AAAs.9 These immunoinflammatory processes are hypothesized to operate in early phases of the aneurysmal disease, even before true dilatation develops. We therefore tested the hypothesis that plasma levels of IL-6 correlate with abdominal aortic diameter in clinically stable subjects without aortic dilatation.
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Methods |
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Patients
Outpatients older than 50 years of age referred to the Noninvasive Cardiac Laboratory of the Brigham and Women's Hospital for a transthoracic echocardiogram were invited to participate in this study. Patients with a clinical history of active infectious or systemic inflammatory disease or patients taking oral or parenteral corticosteroids were excluded. Overall, 120 subjects agreed to participate in the study. Among these subjects, 7 patients were identified with abdominal aortic dilatation (4 patients with incidental dilatation and 3 patients with previously known abdominal aortic aneurysms [AAAs]). Abdominal aortic dilatation was defined as abdominal aortic diameter >1.3 cm/m2 based on data from a cohort of subjects without cardiovascular disease.10 Before the imaging procedures, individual data concerning atherosclerosis risk factors, prior cardiovascular history, and other comorbidities were obtained. The protocol was reviewed and approved by the Human Research Committee of the Brigham and Women's Hospital and informed written consent was obtained from all patients.
Aorta Imaging
Two experienced ultrasonographers, using commercially available
equipment (Hewlett-Packard Sonos 2500, Hewlett-Packard Medical
Products) and a 2.7/3.5-MHz transducer, performed the ultrasound
evaluations. The patients were examined in the supine flexed position,
to relax the abdominal wall. The abdominal aorta was imaged from the
xyphoid process to the periumbilical level, including the aortic
bifurcation whenever possible. Longitudinal and lateral views of the
abdominal segments at the maximum 2-dimensional diameter were
recorded on standard S-VHS videotape for off-line analysis.
The best images in each location were digitized and blindly evaluated
with a custom written software program. Luminal size of the abdominal
aorta was measured at the periumbilical level, corresponding to the
infrarenal segments. The echo-free lumen of the vessel was measured
between the inner trailing edge of the anterior wall and the inner
leading edge of the posterior wall, at the peak of the
electrocardiographic R wave to avoid pulsatile cycle variations. Aortic
diameter indexed to body surface area was used for statistical
analysis. Intraobserver variability and interobserver
variability were calculated in a subset of 30 patients and were <5%
and <10%, respectively.
Blood Measurements
EDTA-anticoagulated blood was obtained by using a 19-gauge
butterfly needle and immediately centrifuged for 20 minutes at
2500 rpm. Aliquots were stored at -70°C. IL-6 was measured in
duplicate by the sandwich ELISA technique (Immunotech). Serum
amyloid A (SAA) was measured by a nephelometric method (Dade Behring)
on the BNII analyzer that possesses a sensitivity down to 0.8
mg/mL. C-reactive protein (CRP), total homocysteine, total
cholesterol, LDL and HDL cholesterol,
Lp(a), and apoB were also assayed, as described
elsewhere.4 11 12 13
Statistical Analysis
Skewed variables underwent logarithmic transformation,
resulting in a near normal distribution. The associations between
indexed aortic diameters and serum levels of IL-6, SAA, CRP, total
homocysteine, and lipids were evaluated by Pearson correlation
coefficients. In addition, subjects without aortic dilatation were
dichotomized into 2 groups according to low (<0.84
cm/m2) or high (
0.84
cm/m2) indexed aortic diameters,
representing the median of the sample. The significance of
any differences in values on the categorized aortic diameter groups
(low and high) and in patients with abdominal aortic dilatation was
computed by using 1-way analysis of variance. A
multivariate stepwise regression model adjusted for
age, history of hypertension, diabetes or
hypercholesterolemia, family history of
premature ischemic heart disease, smoking, angina pectoris,
previous myocardial infarction, and lipid and nonlipid risk factors was
created to identify potential independent correlates of indexed aortic
diameter. A 2-tailed P<0.05 was considered statistically
significant.
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Results |
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Patient Characteristics
Approximately half of the 120 subjects had a history of hypertension or hypercholesterolemia, and 66% were past or present smokers (Table 1
). Previous myocardial infarction had
occurred in 24 (20%) patients and 20 (16%) had a clinical history
consistent with angina pectoris. Reasons for ordering the
echocardiogram included left ventricular function
evaluation (22%), valvular assessment (21%), coronary
artery disease (12%), preoperative evaluation (6%),
arrhythmia (5%), or other (34%).
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IL-6 levels were not normally distributed and underwent logarithmic
transformation, resulting in a near normal distribution. Mean and
median IL-6 levels for this group were 18 and 15.4 pg/mL, respectively.
The lipid profile and other serum measurements are described in Table 1
. Indexed abdominal aortic diameter among patients with aortic
dilatation (n=7) and without aortic dilatation (n=113) was 2.1±0.6 and
0.86±0.1 cm/m2, respectively
(P<0.01). No severe abdominal aortic occlusive disease was
identified within this cohort.
Association Between Aortic Diameters and Serum
Measurements
Among the 113 participants without aortic dilatation, indexed
aortic diameter was positively associated with serum levels of IL-6
(P<0.01), SAA (P<0.01), and total homocysteine
(P=0.01) (Table 2). Adjustment
for age did not substantially alter these correlations. Of note, none
of the serum lipid measurements [total, LDL and HDL
cholesterol, Lp(a) and apoB] correlated with indexed
aortic diameter. Although CRP levels were strongly associated with SAA
levels (r=0.60; P<0.001), associations between
CRP levels and indexed aortic diameters were also nonsignificant.
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Figure 1 displays the linear regression
line and 95% confidence interval between circulating levels of IL-6
and indexed abdominal aortic diameter among patients without aortic
dilatation (Pearson coefficient=0.28; P=0.002). In addition,
log IL-6 values increased in a stepwise fashion among groups of aortic
size (low and high aortic dimension as defined in Methods) and peaked
in patients with aortic dilatation (2.3±1.2 versus 2.7±0.9 versus
3.2±0.9 pg/mL, respectively, P for trend=0.039; Figure 2).
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Adjusted Associations
In multivariate regression analysis
adjusted for age, hypertension, diabetes, smoking, history of
myocardial infarction or angina, and lipid and nonlipid serum
measurements, the only significant correlates of indexed aortic
diameter were plasma concentrations of IL-6 (P=0.02), SAA
(P=0.001), and total homocysteine (P<0.001).
These variables explained 26% of the variance in indexed aortic
diameter (Table 3).
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Discussion |
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These data indicate that plasma concentration of IL-6, SAA, and total homocysteine increase in a stepwise fashion with abdominal aortic dimension among subjects with normal aortic size. With regard to IL-6 and SAA, these findings suggest that inflammatory cytokines and acute-phase reactants may play a role in early phases of AAA pathogenesis, even before frank dilation of the abdominal aorta is established. Our data support the notion that chronic inflammation participates in the pathogenesis of asymptomatic aortic disease. With regard to total homocysteine levels, these data suggest a role of this amino acid in the pathogenesis of aortic disease as well.
Previous studies have evaluated levels of circulating
inflammatory markers in different atherosclerotic syndromes. Recent
data from the Physicians' Health Study, for example, indicate that
baseline levels of CRP predict future risk of developing myocardial
infarction, stroke,4 and symptomatic
peripheral arterial disease.5
Levels of IL-67 and SAA1 are increased among
patients with unstable angina and identify patients with a worse
short-term prognosis. In addition, Szekanecz et al9
demonstrated that tissue culture supernatants from human
atherosclerotic AAAs produce significantly more IL-6 and interferon-
than supernatants from normal aortic tissue. In a similar manner,
Juvonen et al8 recently demonstrated that levels of
circulating IL-6, IL-2, and tumor necrosis factor-
are elevated in
patients with AAA, compared with controls, although a substantial
overlap in individual levels was observed between groups. IL-6 may
derive from infiltrative white blood cells or from intrinsic vascular
wall cells, such as smooth muscle cells.14 There is a
growing body of evidence that suggests that
cytokine-induced tissue inflammation plays an important
role in the pathogenesis and progression of AAA.15 For
example, a range of inflammatory cytokines including tumor
necrosis factor- and IL-6 can upregulate matrix metalloproteinases
by macrophages. Such enzymes have been shown to be present
in human aortic aneurysm walls,16 17 18 19 and
can degrade specific components of the extracellular matrix. McMillan
et al20 explored the relation between extracellular
remodeling with aortic diameter and elegantly demonstrated that
messenger RNA transcript levels of type IV collagenase
differ according to abdominal aortic dimension. Recently, Allaire et
al21 demonstrated that decreased levels of matrix
metalloproteinases induced by overexpression of plasminogen
activator inhibitor-1 can prevent
aneurysm development and rupture. Our data thus extend previous
findings, as they address the hypothesis that elevated inflammatory
markers correlate with aortic dimension in a cohort of stable
outpatients without fully developed aortic dilatation. Furthermore, no
other clinical characteristic or serum measurement, except for total
homocysteine levels, was associated with abdominal aortic dimension in
this sample.
The positive association between plasma concentration of total homocysteine with abdominal aortic diameter concurs with a growing body of evidence that suggests that levels of total homocysteine are associated with increased risk of arterial occlusions and correlate with the extent of atherosclerotic disease.22 In this regard, Malinow et al23 demonstrated an increased prevalence of hyperhomocyst(e)inemia among patients with peripheral arterial occlusive disease, compared with elderly controls. Recently, Robinson et al24 have also demonstrated that elevated homocysteine concentrations were associated with an increased risk of vascular disease independent of several traditional cardiovascular risk factors. Further, case reports suggest an association between hyperhomocysteinemia and multiple aneurysms.25 The mechanisms by which homocysteine could cause vascular damage and ultimately reflect vascular dimensions are unclear. Several in vitro studies suggest that the presence of reduced forms of homocysteine may induce endothelial injury,26 27 inhibit endothelium anticoagulant mechanisms,28 and modify composition of LDLs.29
The reasons for the lack of association between CRP levels and aortic size are unclear, as the clinical information provided by CRP and SAA are expected to be similar.1 In this cohort, CRP may be insufficiently specific to uncover association between initial inflammatory processes and vascular remodeling. Differences in clearance of CRP and SAA could partially explain these differences.30 In addition, we cannot exclude that the associations were not detected because of the small sample size.
Some limitations of our study merit consideration. Greater aortic luminal dimension may not necessarily indicate future dilatation. However, ultrasound characteristics that predict progression of atherosclerotic lesions and vascular dilatation have not been established. Indeed, few prospective studies have evaluated independent risk factors for AAA.31 The coexistence of larger luminal dimensions and extraaortic atherosclerosis may have confounded our findings. This possibility seems unlikely because multivariate analysis showed that traditional risk factors and other cardiac comorbidities did not substantially affect the observed associations. Our sample represents a selected population of patients with or at risk for cardiovascular disease. We cannot ensure that mild or subclinical viral or bacterial infection may have increased circulating levels of IL-6 in this cohort of stable outpatients, although every attempt was made to avoid this scenario. Even so, we believe that this would probably not affect the correlations described in these data, and if so, would most likely reduce the associations between inflammatory markers and aortic dimensions.
In summary, our data indicate that IL-6, SAA, and total homocysteine levels are associated with abdominal aortic dimension even in subjects without aortic dilatation. Although the relation between atherosclerosis and AAA is debatable, our findings suggest that some of the inflammatory markers commonly associated with atherothrombotic syndromes1 2 3 4 5 6 may also be involved in early phases of aneurysmal disease. Further studies are necessary to address whether increased circulating levels of these markers can predict progression of dilatation and may identify subgroups of patients in whom more careful follow-up should be planned.
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Acknowledgments |
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Supported in part by a grant from the National Institutes of Health (54759). Dr Rohde was supported by Capes/Brasilia-Brazil. We thank Dade Behring for the generous contribution of reagents for the SAA and CRP assays.
Received July 21, 1998; accepted December 3, 1998.
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