Download Impaired Responsiveness to NO in Newly Diagnosed Patients With

Impaired Responsiveness to NO in Newly Diagnosed
Patients With Rheumatoid Arthritis
Robert Bergholm, Marjatta Leirisalo-Repo, Satu Vehkavaara, Sari Mäkimattila,
Marja-Riitta Taskinen, Hannele Yki-Järvinen
Downloaded from http://atvb.ahajournals.org/ by guest on August 3, 2017
Objective—Cardiovascular disease is the major cause of excessive mortality in patients with rheumatoid arthritis (RA). We
determined whether endothelial dysfunction characterizes patients with newly diagnosed RA (n⫽10) compared with
normal subjects (control group, n⫽33) and whether it is reversible with 6 months of anti-inflammatory therapy.
Methods and Results—Endothelial function was determined by measuring vasodilatory responses to intrabrachial artery
infusions of acetylcholine (ACh at 7.5 and 15 ␮g/min, low and high dose, respectively), an endothelium-dependent
vasodilator, and to sodium nitroprusside (SNP, 3 and 10 ␮g/min), an endothelium-independent vasodilator. Before
treatment, blood flow responses (fold increase in flow) to low-dose SNP were 30% lower in the RA versus the control
group (4.1⫾0.4-fold versus 5.9⫾0.5-fold, respectively), and responses to high-dose SNP were 34% lower in the RA
group versus the control group (5.1⫾0.6-fold versus 7.7⫾0.7-fold, respectively; P⬍0.001). The responses to low-dose
ACh were 50% lower in the RA group versus the control group (3.0⫾0.5-fold versus 6.6⫾0.7-fold, respectively), and
responses to high-dose ACh were 37% lower in the RA group versus the control group (5.0⫾0.4-fold versus
7.9⫾0.8-fold, respectively; P⬍0.001). After therapy, clinical and laboratory markers of inflammation had significantly
decreased. Blood flow responses to ACh increased significantly (P⫽0.02).
Conclusions—We conclude that newly diagnosed patients with RA have vascular dysfunction, which is reversible with
successful therapy. Therefore, early suppression of inflammatory activity may reduce long-term vascular damage.
(Arterioscler Thromb Vasc Biol. 2002;22:1637-1641.)
Key Words: atherosclerosis 䡲 blood vessels 䡲 vasodilatation
I
n recent years, coronary artery disease has been recognized
as the major cause of excess morbidity and mortality in
patients with rheumatoid arthritis (RA).1–5 Because of parallels between inflammatory/autoimmune diseases and atherosclerosis, it has been suggested that various inflammatory
mediators may contribute to vascular dysfunction in patients
with RA.6 The similarities include increases in circulating
concentrations of adhesion molecules, proinflammatory cytokines, and acute-phase proteins in patients with RA as well
as in subjects with cardiovascular risk factors or overt
cardiovascular disease.6 – 8 In humans, local administration of
tumor necrosis factor (TNF)-␣ and interleukin-1␤ increases
basal NO-dependent venodilatation but impairs endotheliumdependent venodilatation induced by bradykinin.9 These experimental data suggest that inflammatory disorders could
predispose an individual to cardiovascular disease via blunting of endothelium- and NO-dependent vasodilatation. However, the pathophysiological relevance of these data is uncertain, because it is unknown whether in vivo endothelial
dysfunction indeed characterizes chronic human inflammatory diseases such as RA. In the present study, we determined
whether blood flow responses to intra-arterial endotheliumdependent and -independent vasodilators are altered in untreated patients with newly diagnosed RA and, if so, whether
vascular dysfunction can be ameliorated by antiinflammatory therapy.
Methods
Subjects
Ten patients with early RA (duration of symptoms ⱕ18 months)
were studied before and 6 months after the initiation of therapy.
Before the first vascular function study, no patient had received
treatment with disease-modifying antirheumatic drugs (DMARDs)
or oral prednisone. A total of 33 matched normal subjects were
studied as a control group. Clinical and biochemical characteristics
of the study groups are shown in Table 1. The patients fulfilled the
1987 American College of Rheumatology criteria for RA.10 Eight of
the patients were rheumatoid factor positive. None of the patients
had detectable levels of antinucleolar or anticentromere antibodies.
One of the patients had rheumatoid vasculitis and rheumatoid
nodules. No other patient had extra-articular symptoms or signs of
secondary Sjögren’s syndrome. Two of the patients had erosions at
the time of diagnosis. None of the patients or normal subjects had
hypertension or a history of cardiovascular disease, and none of the
Received June 25, 2002; revision accepted July 15, 2002.
From the Department of Medicine, Divisions of Diabetes (R.B., S.V., S.M., H.Y.-J.), Rheumatology (M.L.-R.), and Cardiology (M.-R.T.), University
of Helsinki, Helsinki, Finland.
Correspondence to Hannele Yki-Järvinen, MD, FRCP, Department of Medicine, Division of Diabetes, University of Helsinki, PO Box 340, FIN-00029
HUCH, Helsinki, Finland. E-mail [email protected]
© 2002 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
1637
DOI: 10.1161/01.ATV.0000033516.73864.4E
1638
Arterioscler Thromb Vasc Biol.
October 2002
TABLE 1. Clinical and Biochemical Characteristics of the
Study Groups
Newly Diagnosed
Before
Treatment
(n⫽10)
Sex, women/men
Age, y
Weight, kg
Body mass index, kg/m
Normal Subjects
(n⫽33)
8/2
27/6
52⫾3
54⫾1
74⫾4
2
After
Treatment
(n⫽10)
74⫾4
74⫾2
27⫾1
27⫾1
26⫾1
Waist/hip ratio
0.87⫾0.02
0.87⫾0.02
0.86⫾0.02
SBP, mm Hg
133⫾7
DBP, mm Hg
Hemoglobin, g/L
132⫾4
135⫾4
76⫾3*
77⫾2
81⫾2
128⫾5**
128⫾3††
140⫾1
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ESR, mm/h
40⫾7***
19⫾2†††‡
S-CRP, mg/L
29⫾10***
8⫾3†††‡
S-TNF-␣, ng/L
3.1⫾0.5***
2.3⫾0.5†‡
No. of tender joints
11⫾2
4⫾1‡
No. of swollen joints
8⫾3
4⫾2
4.4⫾0.8
2.3⫾1.0
Pain (pain scale 0–10 cm)
Smokers
3/10
8⫾1
4⫾1
1.5⫾0.2
11/33
Data are shown as mean⫾SEM.
CRP indicates C-reactive protein; ESR, erythrocyte sedimentation rate;
TNF-␣, tumor necrosis factor ␣; SBP, systolic blood pressure; DBP, diastolic
blood pressure.
*P⬍0.05, **P⬍0.01, ***P⬍0.001 for RA patients before treatment vs
normal subjects. †P⬍0.05, ††P⬍0.01, †††P⬍0.001 for RA patients after
treatment vs normal subjects. ‡P⬍0.05 for RA before vs after treatment.
normal subjects used any drugs. After the basal study, the patients
were started with DMARDs if they had clinically active disease.
Nonsteroidal anti-inflammatory drugs were prescribed as symptomatic therapy. Treatment of the RA patients consisted of methotrexate
in 5 patients and cyclophosphamide in 1 patient with rheumatic
vasculitis. Four patients were on low-dose (5 to 7.5 mg) prednisone,
and 7 used nonsteroidal anti-inflammatory drugs. Before the endothelial function tests, the patients were instructed not to take
acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs for
1 week. Use of naproxen (750 mg) for 1 week11 or infusion of
acetylsalicylic acid12 does not alter vascular responses to intrabrachial artery infusions of acetylcholine (ACh) or sodium nitroprusside
(SNP).
Design
Vascular function was measured after a 10- to 12-hour overnight
fast, as detailed below. Before arterial cannulation, an intravenous
catheter was inserted into the right medial antecubital vein to
withdraw blood samples for measurement of concentrations of serum
lipids and lipoproteins and C-reactive protein, TNF-␣, and the
erythrocyte sedimentation rate. The purpose, nature, and potential
risks of the studies were explained to the patients before their written
informed consent was obtained. The experimental protocol was
approved by the ethics committee of the Helsinki University
Hospital.
Assessment of Endothelium-Dependent and
-Independent Vasodilatation
Vascular function was assessed in forearm resistance vessels by
measuring forearm blood flow responses to intra-arterial infusions of
endothelium-dependent (ACh) and -independent (SNP) vasodilators,
as previously described in detail.13 A 27-gauge unmounted steel
cannula (Coopers Needle Works), connected to an epidural catheter
(Portex), was inserted into the left brachial artery. All drugs were
infused at a constant rate of 1 mL/min with infusion pumps (B.
Braun AG). The subjects rested supine in a quiet environment for 30
minutes after needle placement before blood flow measurements
were begun. Normal saline was first infused for 18 minutes. Drugs
were then infused in the following sequence: SNP (Nitropress,
Abbott Laboratories) at 3 ␮g/min (low dose) and 10 ␮g/min (high
dose) and ACh (Miochol, OMJ Pharmaceuticals) at 7.5 ␮g/min (low
dose) and 15 ␮g/min (high dose). These doses were chosen because
they induce comparable increases in forearm blood flow in normal
subjects.13 Each dose was infused for 6 minutes, and the infusion of
each drug was separated by the infusion of normal saline for 18
minutes, during which blood flow returned to basal values. Forearm
blood flow was recorded for 10 seconds at 15-second intervals
during the last 3 minutes of each drug and saline infusion period with
the use of a mercury-in-rubber strain-gauge venous occlusion plethysmograph (EC 4 Strain Gauge Plethysmograph, Hokanson),
which was connected to a rapid cuff inflator (E 20, Hokanson), an
analog-to-digital converter (McLab/4e, AD Instruments), and a
personal computer, as previously described.13 Blood flow measurements were performed simultaneously in the infused (experimental)
and control arm. Means of the final 5 measurements of each
recording period were used for analysis. Blood pressure and heart
rate were measured before and after the endothelial function test.
Blood flow results during infusion of vasodilators SNP and ACh are
reported as a ratio of blood flow in the experimental arm divided by
the blood flow in the control arm to correct for any differences in
basal flow.14
Serum Lipids, Lipoproteins, and Apoproteins
Serum lipoproteins were isolated by ultracentrifugation as previously
described.15 The concentrations of cholesterol and triglycerides in
serum and lipoprotein subfractions were determined by enzymatic
colorimetric assays (Hoffman-La Roche) with the use of an autoanalyzer (Cobas Mira, Hoffman-La Roche). The concentrations of
serum apoA-I, apoA-II, and apoB were determined by using commercially available immunoturbidimetric assays (BoehringerMannheim for apoA-I and apoA-II and Orion Diagnostica for apoB).
Other Measurements
Serum TNF-␣ concentrations were measured by using a highsensitivity ELISA kit from R&D Systems. The percentage of whole
body fat was measured by a single-frequency bioelectrical impedance device (model BIA-101A, Bio-Electrical Impedance Analyzer
System).
Statistical Analyses
The Student unpaired t test was used to compare single measurements between the patients with RA and the normal subjects. Single
measurements before and after therapy were compared by using the
Student paired t test. Comparison of blood flow responses to the 2
doses of vasoactive drugs was performed by ANOVA for repeated
measures.16 Correlation analyses were calculated by using the
Spearman nonparametric rank correlation coefficient. A value of
P⬍0.05 was considered statistically significant. The calculations
were performed by using the GraphPad Prism, version 2.01, statistical program or Systat, version 10 (SPSS). All data are shown as
mean⫾SEM.
Results
RA Patients Before Treatment Compared With
Normal Subjects
Physical and Biochemical Characteristics
The patients with RA and the normal subjects were similar
regarding age, sex, and body weight. The percentage of whole
body fat was also similar (32⫾2%, 33⫾2%, and 34⫾1%
before and after therapy in patients with RA and in normal
subjects; P⫽NS). At baseline, compared with normal sub-
Bergholm et al
Endothelial Function in Rheumatoid Arthritis
1639
TABLE 2. Serum Lipid, Lipo-, and Apoprotein Concentrations
in Patients With RA and in Normal Subjects
RA Patients
Before
Treatment
After
Treatment
Normal
Subjects
Total
1.20⫾0.23
1.30⫾0.21
1.24⫾0.10
VLDL
0.67⫾0.20
0.80⫾0.21
0.71⫾0.09
Total
5.10⫾0.46
5.00⫾0.69
5.80⫾0.17
LDL
3.24⫾0.34*
3.39⫾0.31
3.85⫾0.15
HDL
1.44⫾0.07
1.49⫾0.19
1.44⫾0.06
HDL2
0.69⫾0.07
0.66⫾0.13
0.72⫾0.05
HDL3
0.72⫾0.06
0.75⫾0.11
0.73⫾0.02
Apo A-I, mg/dL
136⫾7
148⫾6
147⫾4
Apo A-II, mg/dL
34⫾3
36⫾2
35⫾1
Apo B, mg/dL
94⫾9
96⫾11
98⫾4
Triglycerides, mmol/L
Cholesterol, mmol/L
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Data are shown as mean⫾SEM.
*P⬍0.05 for patients with RA before treatment vs normal subjects.
jects, the patients with newly diagnosed RA had higher serum
C-reactive protein and TNF-␣ concentrations and erythrocyte
sedimentation rates (Table 1). Serum lipid and lipoprotein
concentrations are shown in Table 2. Compared with normal
subjects, the patients with RA had significantly lower LDL
cholesterol concentrations.
Vascular Function
Basal blood flows were comparable between the patients with
RA and the normal subjects (2.1⫾0.2 mL/dL per minute for
the RA group versus 1.7⫾0.2 mL/dL per minute in normal
subjects, P⫽NS). The blood flow responses (fold increase in
flow in experimental arm above control arm) to low-dose
SNP were 30% lower in the RA patients versus normal
subjects (4.1⫾0.4-fold versus 5.9⫾0.5-fold, respectively),
and the responses to high-dose SNP were 34% lower in the
RA patients versus normal subjects (5.1⫾0.6-fold versus
7.7⫾0.7-fold, respectively; P⬍0.001 by ANOVA). The responses to low-dose ACh were 50% lower in the RA patients
versus normal subjects (3.0⫾0.5-fold versus 6.6⫾0.7-fold,
respectively), and the responses to high-dose ACh were 37%
lower in the RA patients versus normal subjects (5.0⫾0.4fold versus 7.9⫾0.8-fold, respectively; P⬍0.001 by
ANOVA; Figure). Within the group of patients with RA, the
flow response to ACh was inversely correlated with the
erythrocyte sedimentation rate (r⫽⫺0.56, P⬍0.05).
Effect of Therapy
Physical and Biochemical Characteristics
Body composition did not change during therapy (Table 1).
After 6 months of therapy, clinical and laboratory markers of
inflammation had significantly decreased (Table 1). After
therapy, the concentration of serum LDL cholesterol had
increased slightly and was no longer significantly lower in the
patients with RA than in the normal subjects (Table 2). The
concentrations of other lipids, lipoproteins, and apoproteins
were comparable between the groups.
Forearm blood flow responses to intra-arterial SNP (top) and
ACh (bottom) infusions in patients with RA before (closed circles) and after (closed triangles) anti-inflammatory therapy and
in normal subjects (open circles). ⫻⫻⫻P⬍0.001 for patients
with RA before therapy vs normal subjects (ANOVA for repeated
measures), and ⫹⫹P⬍0.02 for blood flow responses to ACh
before vs after therapy in patients with RA (ANOVA for repeated
measures). *P⬍0.05 and **P⬍0.01 for comparison of patients
with RA before therapy vs normal subjects at individual doses of
ACh and SNP.
Vascular Function
Basal blood flow did not change during therapy (2.1⫾0.1
versus 2.0⫾0.1 mL/dL per minute for RA before versus after
therapy, respectively; P⫽NS). After therapy, endothelial
function improved significantly, as judged from blood flow
responses to low and high doses of ACh (P⫽0.02 for repeated
measures by ANOVA, Figure). The blood flow responses to
SNP increased slightly but not significantly (Figure). After
therapy, the responses to ACh (P⫽0.33) or SNP (P⫽0.062)
were no longer significantly lower than those in the normal
subjects (Figure).
Discussion
In the present study, we tested the hypothesis that RA is
characterized by in vivo vascular dysfunction by measuring
blood flow responses to intra-arterial infusions of ACh and
SNP. The measurements were performed in DMARD naive
patients with newly diagnosed RA and were repeated 6
months later when the patients were on anti-inflammatory
and/or DMARD therapy. The novel finding of the present
study was that compared with normal subjects, early untreated patients with RA had blunted vasodilatory responses
to the endothelium-dependent vasodilator ACh and the endothelium-independent vasodilator SNP. After 6 months of
anti-inflammatory therapy, the vasodilatory responses to ACh
had improved significantly. Although increases in the blood
flow responses to SNP were not statistically significant, the
responses increased and were no longer significantly lower in
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Arterioscler Thromb Vasc Biol.
October 2002
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the RA patients than in the normal subjects. An impaired
vasodilatory response to ACh or shear stress is considered an
early abnormality in vascular function preceding atherosclerosis.17 In the coronary arteries, blunted ACh responses
predict cardiac events in patients without obstructive coronary artery disease.18 In the forearm vascular bed, vasodilatory responses to ACh are blunted in patients with cardiovascular risk factors19,20 and are correlated with the severity of
coronary artery disease.21,22 In autopsy studies, atherosclerosis in the brachial artery has been correlated with atherosclerosis in carotid and coronary arteries.23
The blunted vasodilatory responses in the patients with RA
before therapy imply a decrease in NO bioavailability. This
decrease may be caused by decreased expression of endothelial cell NO synthase (eNOS), lack of substrate or cofactors
for eNOS, alteration in the signaling pathways activating
eNOS, or accelerated degradation of NO by reactive oxygen
species.24 Given that the responses to ACh and SNP were
reduced, the latter mechanism or alternatively blunted responsiveness of smooth muscle to endogenous and exogenous NO
could be responsible. The best documented radical that can
react with NO is superoxide.25 The production of superoxide
is stimulated by cytokines in several cell types, including
vascular smooth muscle cells,26 and has been documented in
human RA.27 However, acutely, cytokines appear to decrease
only endothelium-dependent vasodilatation. In normal subjects, generation of an acute systemic inflammatory response
by Salmonella typhimurium attenuates vasodilatory responses
to bradykinin and ACh but not to the endotheliumindependent agonists verapamil and nitroglycerin.28 In human
veins, acute local application of TNF-␣ and interleukin-1␤
impairs vasodilatory responses to bradykinin and arachidonic
acid but does not affect the vasodilator response of nitroglycerin.9 The present data demonstrating impairment in ACh and
SNP responses suggest that the effects of chronic inflammation in humans differ from the effects of acute interventions
with cytokines on vascular function or that mechanisms other
than accelerated NO degradation, such as defects in the
response of vascular smooth muscle to NO, contributed to
vascular dysfunction.
In the present study, the patients received various antirheumatic and anti-inflammatory therapies, including methotrexate, low doses of corticosteroids, and nonsteroidal antiinflammatory agents. When patients were studied 6 months
later on these treatments, restoration of the blood flow
response was observed (especially response to ACh). Because
of the small number of patients studied, it is not possible to
determine which therapy was most responsible, but this
finding is reminiscent of a recent report of restoration of
vascular endothelial function in primary systemic vasculitis
by immunosuppressive therapy consisting of cyclophosphamide and methylprednisolone.29 The blood flow response to
SNP increased slightly and, after treatment, was no longer
significantly lower than that in the normal subjects. The
significant increase in the ACh response but not the SNP
response suggests that treatment increased NO bioavailability
but not the sensitivity of vascular smooth muscle to NO.
The patients with RA had lower LDL cholesterol levels
than did the normal subjects, which is in line with previous
data.30,31 Despite lower LDL cholesterol concentrations, the
patients with RA had blunted blood flow responses to ACh
compared with responses in normal subjects before therapy.
The concentration of LDL cholesterol is one of the major
determinants of endothelial function,32,33 and its lowering by
drugs such as statins improves endothelium-dependent vasodilatation.34 In the present study, serum LDL cholesterol, if
anything, was slightly increased by therapy (Table 2), indicating that other factors are likely to explain the improvement
in endothelial function. On the other hand, we did not
determine whether LDL was normal regarding its size and
other characteristics, such as oxidizability. Recently HurtCamejo et al31 reported that RA patients have higher levels of
small dense LDL despite a lower concentration of total LDL
cholesterol. LDL particles from RA patients also had significantly higher binding affinity to glycosaminoglycans, suggesting that LDL particles may become trapped in the vessel
wall matrix and be prone to oxidation. Modified but not
native LDL inhibits endothelium-dependent vascular
relaxation.35
Data have been lacking regarding vascular function in
chronic inflammatory conditions other than those primarily
affecting the vascular wall, such as thromboangiitis obliterans,36 Kawasaki disease,37 Wegener’s granulomatosis or polyarteritis nodosa,29 and primary Raynaud’s phenomenon.38
The present data add RA to the list of diseases characterized
by vascular dysfunction. Early suppression of systemic inflammation in RA not only diminishes disease activity but
also appears to improve vascular function and may therefore
decrease the risk of cardiovascular complications of these
patients.
Acknowledgments
This study was supported by grants from the Academy of Finland
(S.V., H.Y.-J.), the Sigrid Juselius Foundation (H.Y.-J.), the Novo
Nordisk Foundation (H.Y.-J.), the Finnish Foundation for Cardiovascular Research (S.V.), and the Medical Society of Finland (R.B.).
We gratefully acknowledge Sari Haapanen, Kati Tuomola, and Katja
Tuominen for excellent technical assistance.
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Impaired Responsiveness to NO in Newly Diagnosed Patients With Rheumatoid Arthritis
Robert Bergholm, Marjatta Leirisalo-Repo, Satu Vehkavaara, Sari Mäkimattila, Marja-Riitta
Taskinen and Hannele Yki-Järvinen
Arterioscler Thromb Vasc Biol. 2002;22:1637-1641; originally published online August 15,
2002;
doi: 10.1161/01.ATV.0000033516.73864.4E
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