Download Arterial Stiffness in Chronic Inflammatory Diseases

Arterial Stiffness in Chronic Inflammatory Diseases
Mary J. Roman,, Richard B. Devereux, Joseph E. Schwartz, Michael D. Lockshin, Stephen A. Paget,
Adrienne Davis, Mary K. Crow, Lisa Sammaritano, Daniel M. Levine, Beth-Ann Shankar,
Elfi Moeller, Jane E. Salmon
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Abstract—Chronic inflammatory diseases are associated with premature atherosclerosis; however, it is unknown whether
arterial stiffness is increased in this setting, possibly as a manifestation of vascular disease preceding and/or independent
of atherosclerosis. Carotid ultrasonography and radial applanation tonometry were performed in 101 patients with
systemic lupus erythematosus, 80 patients with rheumatoid arthritis, and 105 healthy control subjects. The 3 groups were
comparable in age, gender, and carotid artery absolute and relative wall thickness. Atherosclerotic plaque was more
common in lupus (46%) and rheumatoid arthritis (38%) patients than in controls (23%) (P⬍0.003). Although control
subjects had higher central and peripheral blood pressures, arterial stiffness was increased in patient groups compared
with controls (lupus, rheumatoid arthritis, controls, respectively: ␤: 3.36 versus 3.22 versus 2.60, P⬍0.001; Young’s
modulus: 441 versus 452 versus 366 mm Hg/cm, P⫽0.004; Peterson’s elastic modulus: 278 versus 273 versus
216 mm Hg, P⬍0.001) after adjustment for differences in mean brachial pressure. In multivariate analysis involving the
entire population, arterial stiffness was independently related to age, serum glucose, and the presence of chronic
inflammatory disease. In multivariate analysis restricted to the patients, arterial stiffness was independently related to
age at diagnosis, disease duration, serum cholesterol, and C-reactive protein (and IL-6, when substituted for C-reactive
protein). When analyses were repeated in the 186 study subjects without carotid plaque, arterial stiffness remained
significantly elevated in patient groups after adjustment for differences in age and mean brachial pressure. In conclusion,
arterial stiffness is increased in chronic inflammatory disorders independent of the presence of atherosclerosis and is
related to disease duration, cholesterol, and the inflammatory mediator C-reactive protein and the cytokine that
stimulates its production, IL-6. (Hypertension. 2005;46:194-199.)
Key Words: arterial pressure 䡲 arteriosclerosis 䡲 carotid arteries 䡲 elasticity 䡲 vascular disease
A
sclerosis, was not related to C-reactive protein or other
circulating mediators of inflammation independent of traditional cardiovascular disease risk factors in the Framingham
Offspring Study.12
Chronic inflammatory diseases might be associated with
arterial stiffness, possibly as a manifestation of premature
atherosclerosis.13 In 2 recent studies in small numbers of
patients with rheumatoid arthritis and control subjects, arterial stiffness was marginally increased in patients after
adjustment for traditional risk factors in one study,14 and
significantly increased in another study involving 14 young
patients with no cardiovascular disease risk factors.15 Thus
the present study was designed to determine whether arterial
stiffness is increased in a large sample of patients with
chronic inflammatory diseases in comparison to healthy
control subjects and to determine whether arterial stiffness
associated with inflammation is independent of both traditional cardiovascular disease risk factors and of the presence
of atherosclerosis.
rterial stiffening is caused by structural changes within
the walls of the major conduit arteries resulting in an
increase in pulse wave velocity. Systolic and pulse pressures
are increased because of an alteration in the timing of
reflected waves. Arterial stiffening occurs as a consequence
of aging1 and is increased in the setting of risk factors for
atherosclerosis such as hypertension,2 diabetes,3 hypercholesterolemia,4,5 and smoking.6 Furthermore, arterial stiffening
predicts cardiovascular events independent of traditional risk
factor.7,8 Given the relation of inflammation to atherosclerosis, elevated levels of inflammatory mediators might be
associated with arterial stiffening. C-reactive protein was
recently reported to be independently related to higher pulse
wave velocity9 and pulse pressure,10 a surrogate for arterial
stiffening, in 2 healthy British and US populations, respectively, but not to pulse wave velocity in healthy Japanese men
after traditional risk factors were taken into account.11 Flowmediated dilation of the brachial artery, a measure of endothelial function that may be altered in the setting of athero-
Received February 9, 2005; first decision March 1, 2005; revision accepted April 13, 2005.
From the Divisions of Cardiology (M.J.R., R.B.D.) and Rheumatology (M.D.L., S.A.P., A.D., M.K.C., L.S., B.A.S., E.M., J.E.S.) and The Rogosin
Institute (D.M.L.), Weill Medical College of Cornell University, The Hospital for Special Surgery, New York, NY; and the Department of Psychiatry
(J.E.S.), SUNY-Stony Brook, NY.
Correspondence to Mary J. Roman, MD, Division of Cardiology, Weill Medical College of Cornell University, 525 East 68th St, New York, NY 10021.
E-mail [email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000168055.89955.db
194
Roman et al
Methods
Study Population
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The patient population consisted of patients with systemic lupus
erythematosus (SLE) or rheumatoid arthritis (RA) participating in a
study to determine the prevalence and correlates of premature
atherosclerosis in these conditions.13 Patients were sequentially
recruited for the study at the time of regularly scheduled outpatient
visits with their rheumatologist at the Hospital for Special Surgery.
Patients fulfilled strict diagnostic criteria for the presence of SLE16
or RA.17 Control subjects of a comparable age and gender who had
undergone a similar protocol to assess arterial structure and function
were drawn from a longitudinal study of employed individuals.18,19
Patients were excluded based on use of antihypertensive medications
at the time of study; none had renal failure. Hypertensive control
subjects were studied after withdrawal of antihypertensive medications for at least 3 weeks, and, in many instances, several months. A
total of 105 control subjects, 101 patients with SLE, and 80 patients
with RA were eligible for inclusion in the present study. Study
protocols were approved by our institutions’ institutional review
boards; all subjects gave signed informed consent to study
participation.
All patients were interviewed and examined with the use of
standardized data collection instruments. Disease activity and
disease-related damage in SLE patients was assessed with use of the
Systemic Lupus Erythematosus Disease Activity Index20 and the
Systemic Lupus International Collaborating Clinics Damage Index,21
respectively, whereas disease-related damage among RA patients
was assessed by an index of irreversible joint damage.22 Laboratory
evaluation of patients included erythrocyte sedimentation rate, serum
complement (C3 and C4), and high-sensitivity C-reactive protein.
Serum IL-6 was measured with the use of a kit (Biosource
International).
Carotid Ultrasonography
All study participants underwent carotid ultrasonography; all studies
were performed by an experienced research sonographer using an
identical protocol and interpreted by a single cardiologist. In brief, as
previously described,18 both extracranial carotid arterial systems
were extensively scanned in multiple planes to optimize identification of atherosclerosis defined as discrete plaque protruding into the
lumen ⱖ50% beyond the thickness of the adjacent wall. Intimalmedial thickness (IMT) and lumen diameter were measured from
end-diastolic (minimum dimension) M-mode images of the far wall
of the distal common carotid artery. IMT was never measured in a
location containing plaque (uncommon in the common carotid
artery, which is characterized by laminar flow). Minimum and
maximum arterial diameters were obtained by continuous tracing of
the intima–lumen interfaces of the near and far walls. Arterial
cross-sectional area was calculated as a more comprehensive estimate of vascular volume or mass.18 Relative wall thickness of the
artery was calculated as (2 ⫻ IMT)/end-diastolic diameter. Vascular
strain was calculated as ([maximum diameter ⫺ minimum diameter]/
minimum diameter) ⫻ 100. Brachial blood pressures were obtained
in triplicate and averaged at the end of the ultrasound studies, ie, after
45 to 60 minutes in the supine position in a quiet, darkened room.
Assessment of Arterial Stiffness
Arterial stiffness was estimated from pressure– diameter relations of
the common carotid artery and pressure waveforms obtained by
applanation tonometry of the radial artery with a high-fidelity
transducer; central arterial waveforms and pressures were calculated
by the use of the SphygmoCor device using a generalized transfer
function (AtCor Medical, Sydney, Australia) and calibration using
the brachial mean and diastolic pressures. Orientation and pressure
applied to the transducer were adjusted to achieve optimal applanation of the artery between the transducer and the underlying tissue.
Applanation tonometry has been validated to yield accurate estimates
of intra-arterial pulse pressure by comparison with simultaneous
invasive pressure recordings.23–25 Minimum (end-diastolic) and
maximum (peak systolic) diameters were obtained from carotid
Chronic Inflammation and Arterial Stiffness
195
TABLE 1. Demographic Characteristics of Patient and
Control Groups
Variable
No.
Age, y
Gender, % female
BSA, m2
Hypertension, %
Control
SLE
RA
ANOVA or ␹2
105
101
80
47⫾8
45⫾13
45⫾12
95
95
99
0.36
1.75⫾0.17
1.74⫾0.20
1.69⫾0.14
0.047
5
10
3
0.091
0.50
Brachial BP, mm Hg
Systolic
110⫾16
105⫾14*
106⫾15
0.026
Diastolic
74⫾9
65⫾9‡
68⫾8‡
⬍0.001
Mean
88⫾10
78⫾10‡
81⫾10†
⬍0.001
Pulse
37⫾11
39⫾10
38⫾11
0.27
Systolic
100⫾15
93⫾12†
97⫾16
0.003
Diastolic
75⫾9
67⫾9‡
69⫾8‡
⬍0.001
Mean
86⫾11
78⫾10†
81⫾10†
⬍0.001
Pulse
25⫾10
27⫾8
29⫾13
66⫾11
74⫾12‡
71⫾10†
Aortic BP, mm Hg
Heart rate, bpm
Current smoking, %
17
12
Cholesterol, mg/dL
202⫾40
189⫾40
5
201⫾43
0.086
⬍0.001
0.054
0.043
BP indicates blood pressure; BSA, body surface area; RA, rheumatoid
arthritis; SLE, systemic lupus erythematosus.
*P⬍0.05 vs control; †P⬍0.01 vs control; ‡P⬍0.001 vs control in post hoc
testing for multiple comparisons.
ultrasonography performed immediately before applanation tonometry with the position of the subject and ambient environment
unchanged. Three measures of arterial stiffness were evaluated: (1)
arterial stiffness index (␤):26,27 ln(Ps/Pd)/([Ds⫺Dd]/Dd), where Ps and
Pd are aortic systolic and diastolic pressures, respectively, and Ds and
Dd are carotid systolic and diastolic diameters, respectively; (2)
Young’s modulus:28 ([Ps⫺Pd]/[Ds⫺Dd])⫻(Dd /IMTd), where IMTd is
common carotid artery far wall thickness at end diastole; and (3)
Peterson’s elastic modulus:29 Ep⫽([Ps⫺Pd]/[Ds⫺Dd])⫻Dd.
These measures provide indices of regional arterial stiffness under
the vessel’s usual loading conditions (Peterson’s elastic modulus) or
adjusted for the effects of arterial wall thickening (Young’s modulus)
and distending pressure (stiffness index). The arterial stiffness index
is considerably less pressure-dependent than is Peterson’s elastic
modulus.30
Statistical Analyses
Comparisons were made between the three groups using ␹2 statistic
for categorical variables and 1-way analysis of variance for continuous variables with post hoc testing for multiple comparisons
(Scheffé). Continuous variables are expressed with the standard
deviation as the index of dispersion and the standard error for
adjusted means. Independence of association with arterial stiffness
was performed by stepwise linear regression analysis using those
variables found to have a bivariate relation (P⬍0.1) to arterial
stiffness as potential predictors.
Results
Comparison of Demographics Characteristics and
Arterial Structure
By design, patients and control subjects were comparable in
age and gender (Table 1). Weight and height were similar in
the 3 groups. Although the rates of diagnosed hypertension
did not differ among the 3 groups, both brachial and central
196
Hypertension
July 2005
TABLE 2. Common Carotid Artery Structure in Patient and
Control Groups
Variable
No.
Diastolic diameter, mm
Control
SLE
RA
ANOVA
or ␹2
105
101
80
5.24⫾0.5
5.45⫾0.47*
5.28⫾0.47
0.01
Systolic diameter, mm
5.85⫾0.60
6.06⫾0.56*
5.89⫾0.52
0.014
IMT, mm
0.63⫾0.13
0.63⫾0.16
0.61⫾0.16
0.67
Relative wall thickness
0.24⫾0.05
0.23⫾0.06
0.23⫾0.06
0.67
CSA, mm/m2
6.76⫾1.92
7.02⫾2.24
6.78⫾2.07
0.62
Plaque, %
23
Strain, %
11⫾3
46
11⫾4
38
0.003
11⫾3
0.90
CSA indicates cross-sectional area; IMT, intimal-medial thickness.
*P⬍0.05 vs control.
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diastolic and mean pressures were higher in the control
subjects, whereas pulse pressures were similar. Heart rate was
higher in patients than in control subjects. Current smoking
tended to be more prevalent among the control subjects.
Diabetes was present in 3 patients and in no control subjects.
Although carotid artery lumen diameters were slightly larger
in the patients with systemic lupus erythematosus than in
control subjects, there were no differences between the 3
groups in absolute and relative wall thickness or in overall
arterial cross-sectional area (Table 2). Atherosclerotic plaque
was found more commonly in the patients.
Comparison of Arterial Stiffness
In view of differences in blood pressures between patients
and control subjects, and to avoid autocorrelation, estimates
of arterial stiffness were adjusted for differences in mean
brachial blood pressure. All 3 estimates of arterial stiffness
were significantly greater in the 2 patient populations than in
the control group (Figure, Table 3). Heart rate did not relate
to the 3 estimates of arterial stiffness; therefore, further
adjustment for heart rate did not alter the findings.
Because atherosclerosis promotes arterial stiffening, analyses were repeated in the control subjects and SLE and RA
patients without atherosclerotic plaque. Control subjects were
older (46⫾9 years) than the SLE and RA patients (39⫾9 and
40⫾11, respectively; P⬍0.001), with higher mean brachial
blood pressures (85⫾10 versus 78⫾11 and 78⫾7 mm Hg,
respectively; P⬍0.001). After adjustment for differences in
age and mean brachial blood pressure, all 3 measures of
arterial stiffness remained elevated in patients without plaque
compared with control subjects without plaque (Table 3).
Further adjustment of the arterial stiffness index and Peterson’s elastic modulus for carotid wall thickness or crosssectional area had no effect on results.
Determinants of Arterial Stiffness
Independent correlates of the arterial stiffness index (␤) in the
entire population were age, fasting glucose level, and the
presence of either systemic lupus erythematosus or rheumatoid arthritis (Table 4). When analyses were restricted to the
patients, age at diagnosis, duration of disease, level of
C-reactive protein, and fasting, serum cholesterol entered the
model (Table 5). In models predicting either Peterson’s
elastic modulus or Young’s modulus, mean arterial pressure
also entered the equation, supporting the lesser pressure
dependence of the arterial stiffness index relative to the other
estimates of arterial stiffness; the association between inflammatory disease and increased arterial stiffness was significant
in all analyses. Substitution of erythrocyte sedimentation rate,
C3 or C4 for C-reactive protein weakened the model. In
contrast, IL-6, which stimulates the production of acute phase
reactants including C-reactive protein, entered the model
when substituted for C-reactive protein. Among patients with
SLE, arterial stiffness was not related to either disease
activity or disease-related damage, as assessed by the SLE
Disease Activity Index and Systemic Lupus International
Collaborating Clinics Damage Index, respectively. Among
patients with RA, arterial stiffness was not related to irreversible joint damage.
Discussion
Arterial stiffness index (mean⫾95% confidence interval) in control subjects and in patients with systemic lupus erythematosus
(SLE) and rheumatoid arthritis (RA).
The present study is the first to demonstrate that arterial
stiffness is increased in the chronic inflammatory diseases
SLE and RA relative to a control population independent of
traditional risk factors for atherosclerosis. Furthermore, arterial stiffening is not attributable to the premature atherosclerosis detected in these diseases. Rather, the similarity in
vascular structure in the 3 groups and the confirmation of
findings when distending pressure is taken into account by
use of the arterial stiffness index suggest an alteration in
underlying physical properties of the vessel wall and/or
vascular tone in the setting of chronic inflammation even in
the absence of atherosclerosis. The independent association
of fasting glucose with arterial stiffness noted in the present
study is in keeping with earlier observations in diabetic
patients3 and in the general population,31 possibly as a
consequence of accumulation of advanced glycation endproducts.32 The associations of disease duration and level of
C-reactive protein with arterial stiffening in patients with
SLE and RA suggest that the cumulative burden of inflam-
Roman et al
TABLE 3.
Chronic Inflammation and Arterial Stiffness
197
Estimates of Arterial Stiffness in Patient and Control Groups
Entire Population
Variable
Control
SLE
RA
105
101
80
Stiffness index (␤)
2.60⫾0.13
3.36⫾0.13
3.22⫾0.14
Young’s modulus, mm Hg/cm
365⫾19
441⫾19
452⫾21
0.004
Elastic modulus, mm Hg
216⫾11
278⫾11
273⫾12
⬍0.001
No.
ANCOVA*
⬍0.001
Control Subjects and Patients Free of Atherosclerotic Plaque
Variable
Control
No.
SLE
RA
ANCOVA†
81
55
50
Stiffness index (␤)
2.39⫾0.11
3.08⫾0.13
2.99⫾0.14
Young’s modulus, mm Hg/cm
347⫾20
430⫾24
442⫾24
0.006
Elastic modulus, mm Hg
196⫾9
252⫾11
248⫾11
⬍0.001
⬍0.001
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*Adjusted for differences in mean brachial artery pressure; data are presented as adjusted
means⫾SE.
†Adjusted for differences in age and mean brachial artery pressure; data are presented as adjusted
means⫾SE.
mation is of primary importance in this abnormality. The
independent relation of cholesterol to arterial stiffness in our
patients with chronic inflammatory diseases is of interest
given the recent observation that low-grade systemic inflammation may be a primary mediator of increased arterial
stiffness in individuals with hypercholesterolemia.5
To date, few studies have evaluated arterial function in
chronic inflammatory diseases. Carotid femoral pulse wave
velocity was determined in 220 women with SLE participating in the Pittsburgh SLE Registry and was significantly
related to mean arterial pressure, age, impaired fasting glucose, low white blood cell count, and serum creatinine in
postmenopausal women, and to carotid atherosclerosis, C3
level, and lack of use of hydroxychloroquine in premenopausal women.33 The study lacked a control population to
determine whether arterial stiffness was actually increased in
women with SLE. Brachial artery flow-mediated dilatation, a
measure of endothelial function, was reduced in 62 patients
with SLE in comparison to 38 control subjects in a recent
study from the United Kingdom and was not related to
specific disease attributes, although C-reactive protein was
not evaluated.34 In contrast, a small study of 25 patients with
RA and 25 control subjects did not detect differences between
the 2 groups in flow-mediated dilatation,35 whereas arterial
TABLE 4. Multivariate Correlates of Arterial Stiffness (␤) in
the Entire Population
Variable
Age (per 10 y)
␤
P
R2 Change
0.485
⬍0.001
0.256
compliance was reduced in a subset of patients, although
results were not adjusted for higher blood pressure in the
patients. In a small study of another chronic inflammatory
disease, systemic vasculitis, pulse wave velocity, and augmentation index, an indirect measure of arterial stiffness,
were increased in comparison to a control population, but
only among those patients with active disease.36 Again, the
relation of these findings to premature atherosclerosis was not
investigated.
Although premature atherosclerosis might be expected to
promote arterial stiffening in chronic inflammatory diseases,
our study indicates that factors other than arterial wall
thickness, as a possible measure of early or diffuse atherosclerosis, or discrete atherosclerotic plaque detectable by
noninvasive ultrasonography, are responsible and are consistent with the hypothesis that C-reactive protein or IL-6, the
cytokine that stimulates its synthesis, has a direct role.
C-reactive protein is deposited in the arterial intima in early
atherosclerotic lesions,37 induces an inflammatory and
atherogenic phenotype in endothelial cells,38,39 interferes with
endothelial progenitor cell survival and function,40 and stimulates vascular smooth muscle cell migration and proliferation.41 The lack of differences in intimal-medial thickness
TABLE 5. Multivariate Correlates of Arterial Stiffness
(␤) in Patients with Systemic Lupus Erythematosus or
Rheumatoid Arthritis
␤
P
Age at diagnosis (per 10 y)
0.453
⬍0.001
0.185
0.205
0.004
0.041
Variable
R2 Change
Glucose, mg/dL
0.247
⬍0.001
0.088
Duration of disease (per y)
Disease status*
0.145
0.006
0.018
C-reactive protein*
0.176
0.032
0.011
Serum cholesterol, mg/dL
0.152
0.030
0.022
*Disease status: 0 indicates control subject; 1, presence of systemic lupus
erythematosus or rheumatoid arthritis.
Model: R⫽0.602; R 2 ⫽ 0.363.
Not in model: mean arterial pressure, serum cholesterol, smoking status,
intimal-medial thickness, and plaque
Model: R⫽0.527; R 2 ⫽ 0.278.
Not in model: mean arterial pressure, serum glucose, smoking status,
intimal-medial thickness, and plaque.
*IL-6 entered the model when substituted for C-reactive protein.
198
Hypertension
July 2005
between our patient and control groups does not preclude the
occurrence of microscopic structural changes within the
extracellular matrix of the vessel walls, which might alter
endothelial cell function and physical properties of the vessel
wall. Furthermore, current ultrasound techniques do not allow
separate measurement of intimal and medial layers, which
may be differentially affected by inflammation. Independent
of the cause of alterations in arterial function in chronic
inflammatory disease, 2 recent studies showed an improvement in endothelial function associated with infliximab therapy42 and a reduction in the augmentation index associated
with atorvastatin therapy43 in small numbers of RA patients.
Perspectives
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Our study documents substantial increases in arterial stiffness
in patients with systemic lupus erythematosus and rheumatoid arthritis independent of the presence of atherosclerotic
plaque and traditional risk factors. The association of arterial
stiffening with disease duration and circulating levels of
C-reactive protein and IL-6 implicates chronic inflammation
as important mediators of this process. The cross-sectional
nature of our study limits our ability to determine whether
arterial stiffening precedes the development of atherosclerosis. However, the independent prognostic usefulness of arterial stiffness documented in other populations6,7,44 suggests
that noninvasive measurement of arterial stiffness might be
used as a biomarker for increased vascular risk in chronic
inflammatory diseases and as a target of treatment efficacy.
Acknowledgments
Supported by National Institutes of Health grant AR 45591.
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Hypertension. 2005;46:194-199; originally published online May 23, 2005;
doi: 10.1161/01.HYP.0000168055.89955.db
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